Heterocyclic compounds that are inhibitors of the enzyme DPP-IV

ABSTRACT

The present invention relates to therapeutically active and selective inhibitors of the enzyme DPP-IV of formula I, pharmaceutical compositions comprising the compounds and the use of such compounds for and the manufacture of medicaments for treating diseases that are associated with proteins that are subject to inactivation by DPP-IV, such as type 2 diabetes and obesity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/186,498 filed on Jun. 28, 2002 and claims priority of U.S.provisional application Nos. 60/309,621 filed Aug. 1, 2001 and60/356,631 filed Feb. 8, 2002 and claims priority of Danish applicationnos. PA 2001 01049 filed Jul. 3, 2001 and PA 2002 00180 filed Feb. 6,2002, the contents of which are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to therapeutically active and selectiveinhibitors of the enzyme DPP-IV, pharmaceutical compositions comprisingthe compounds and the use of such compounds for and the manufacture ofmedicaments for treating diseases that are associated with proteins thatare subject to inactivation by DPP-IV, such as type 2 diabetes andobesity.

BACKGROUND OF THE INVENTION

Dipeptidyl peptidase-IV (DPP-IV), a serine protease belonging to thegroup of post-proline/alanine cleaving amino-dipeptidases, specificallyremoves the two N-terminal amino acids from proteins having proline oralanine in position 2.

Although the physiological role of DPP-IV has not been completelyestablished, it is believed to play an important role in neuropeptidemetabolism, T-cell activation, gastric ulceration, functional dyspepsia,obesity, appetite regulation, impaired fasting glucose (IFG) anddiabetes.

DPP-IV has been implicated in the control of glucose metabolism becauseits substrates include the insulinotropic hormones Glucagon likepeptide-1 (GLP-1) and Gastric inhibitory peptide (GIP). GLP-1 and GIPare active only in their intact forms, removal of their two N-terminalamino acids inactivates them.

In vivo administration of synthetic inhibitors of DPP-IV preventsN-terminal degradation of GLP-1 and GIP, resulting in higher plasmaconcentrations of these hormones, increased insulin secretion and,therefore, improved glucose tolerance. Therefore, such inhibitors havebeen proposed for the treatment of patients with Type 2 diabetes, adisease characterised by decreased glucose tolerance. (Hoist, J. J.,Deacon, C. F. Diabetes 47 (1998) 1663-70).

Diabetic dyslipidemia is characterized by multiple lipoprotein defects,including moderately high serum levels of cholesterol and triglycerides,small LDL particles, and low levels of HDL cholesterol. The results ofrecent clinical trials reveal beneficial effects of cholesterol-loweringtherapy in diabetic and non-diabetic patients, thus supporting increasedemphasis on treatment of diabetic dyslipidemia. The National CholesterolEducation Program's Adult Treatment Panel II advocated this need forintensive treatment of diabetic dyslipidemia.

Obesity is a well-known risk factor for the development of many verycommon diseases such as atherosclerosis, hypertension and diabetes. Theincidence of obese people and thereby also these diseases is increasingthroughout the entire industrialised world.

Except for exercise, diet and food restriction no convincingpharmacological treatment for reducing body weight effectively andacceptably currently exist. However, due to its indirect but importanteffect as a risk factor in mortal and common diseases it will beimportant to find treatment for obesity or appetite regulation. Evenmild obesity increases the risk for premature death, diabetes,hypertension, atherosclerosis, gallbladder disease and certain types ofcancer. In the industrialised western world the prevalence of obesityhas increased significantly in the past few decades. Because of the highprevalence of obesity and its health consequences, its prevention andtreatment should be a high public health priority. At present a varietyof techniques are available to effect initial weight loss.Unfortunately, initial weight loss is not an optimal therapeutic goal.Rather, the problem is that most obese patients eventually regain theirweight. An effective means to establish and/or sustain weight loss isthe major challenge in the treatment of obesity today.

Several compounds have been shown to inhibit DPP-IV, but all of thesehave limitations in relation to the potency, stability, selectivity,toxicity, and pharmacodynamic properties. Thus, there is a need for theprovision of DPP-IV inhibitors that are superior with respect to one ormore of the above listed properties, and which will be useful for thetreatment of conditions, which may be regulated or normalised byinhibition of DPP-IV.

SUMMARY OF THE INVENTION

The present invention consists of novel purine derivatives, attached atposition 8 of the purine skeleton to a cyclic diamine, at either one orthe other of the amino groups of the diamine. The compounds of thepresent invention are thus not amino acid derivatives, such as thepresently known DPP-IV inhibitors, but consist of structural elementshitherto unrelated to DPP-IV inhibition, and as such they representnovel solutions to the problem of finding an optimal DPP-IV inhibitor.These compounds are potent and selective inhibitors of DPP-IV, and areeffective in treating conditions that may be regulated or normalised viainhibition of DPP-IV. The invention also concerns methods for preparingthe compounds, pharmaceutical compositions comprising the compounds, amethod of inhibiting DPP-IV comprising administering to a patient inneed of such treatment a therapeutically effective amount thereof, thecompounds for use as a pharmaceutical, and their use in a process forthe preparation of a medicament for treating a condition which may beregulated or normalised via inhibition of DPP-IV.

Definitions

The term “DPP-IV” as used herein is intended to mean Dipeptidylpeptidase IV (EC 3.4.14.5, DPP-IV), also known as CD26. DPP-IV cleaves adipeptide from the N terminus of a polypeptide chain containing aproline or alanine residue in the penultimate position. The term“treatment” is defined as the management and care of a patient for thepurpose of combating the disease, condition, or disorder and includesthe administration of a compound of the present invention to prevent theonset of the symptoms or complications, or alleviating the symptoms orcomplications, or eliminating the disease, condition, or disorder.

The term “beta cell degeneration” is intended to mean loss of beta cellfunction, beta cell dysfunction, and death of beta cells, such asnecrosis or apoptosis of beta cells.

The term “C₁-C₁₀ alkyl” as used herein, alone or in combination, refersto a straight or branched, saturated hydrocarbon chain having from 1-10carbon atoms such as but not limited to e.g. methyl, ethyl, n-propyl,isopropyl, n-butyl, sec. Butyl, isobutyl, tert. Butyl, n-pentyl,2-methylbutyl, 3-methylbutyl, n-hexyl, 4-methylpentyl, neopentyl,2,2-dimethylpropyl and the like.

The term “C₂-C₁₀-alkenyl” used herein, alone or in combination, refersto a straight or branched, unsaturated hydrocarbon chain having from2-10 carbon atoms and at least one double bond such as but not limitedto vinyl, 1-propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl andn-hexenyl and the like.

The term “C₂-C₁₀ alkynyl” as used herein, alone or in combination,refers to an unsaturated hydrocarbon chain having from 2-10 carbon atomsand at least one triple bond such as but not limited to —C≡CH, —C≡CCH₃,—CH₂C═CH, —CH₂—CH₂—C≡CH, —CH(CH₃)C≡CH and the like.

The term “C₁-C₁₀-alkoxy” as used herein, alone or in combination isintended to include those C₁-C₁₀-alkyl groups of the designated lengthin either a linear or branched or cyclic configuration linked through anether oxygen having its free valence bond from the ether oxygen.Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy,pentoxy and hexoxy. Examples of branched alkoxy are isopropoxy,sec-butoxy, tert-butoxy, isopentoxy and isohexoxy. Examples of cyclicalkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy andcyclohexyloxy.

The term “C₃-C₁₀ cycloalkyl” as used herein refers to a radical of oneor more saturated cyclic hydrocarbon having from 3-10 carbon atoms suchas but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,adamantyl and the like.

The term “C₃-C₁₀ cycloalkane” as used herein refers to a saturatedcyclic hydrocarbon having from 3-10 carbon atoms such as but not limitedto cyclopropane, cyclobutane, cyclopentane, cyclohexane, adamantane andthe like.

The term “C₅-C₁₀ cycloalkenyl” as used herein refers to a radical of oneor more cyclic hydrocarbon having at least one double bond having from5-10 carbon atoms such as but not limited to cyclopentenyl, cyclohexenyland the like.

The term “C₃-C₇ cycloheteroalkyl” as used herein refers to a radical oftotally saturated heterocycle like a cyclic hydrocarbon containing oneor more heteroatoms selected from nitrogen, oxygen and sulphurindependently in the cycle such as pyrrolidine (1-pyrrolidine,2-pyrrolidine, 3-pyrrolidine, 4-pyrrolidine, 5-pyrrolidine),pyrazolidine (1-pyrazolidine, 2-pyrazolidine, 3-pyrazolidine,4-pyrazolidine, 5-pyrazolidine), imidazolidine (1-imidazolidine,2-imidazolidine, 3-imidazolidine, 4-imidazolidine, 5-imidazolidine),thiazolidine (2-thiazolidine, 3-thiazolidine, 4-thiazolidine,5-thiazolidine), piperidine (1-piperidine, 2-piperidine, 3-piperidine,4-piperidine, 5-piperidine, 6-piperidine), piperazine (1-piperazine,2-piperazine, 3-piperazine, 4-piperazine, 5-piperazine, 6-piperazine),morpholine (2-morpholine, 3-morpholine, 4-morpholine, 5-morpholine,6-morpholine), thiomorpholine (2-thiomorpholine, 3-thiomorpholine,4-thiomorpholine, 5-thiomorpholine, 6-thiomorpholine), 1,2-oxathiolane(3-(1,2-oxathiolane), 4-(1,2-oxathiolane), 5-(1,2-oxathiolane),1,3-dioxolane (2-(1,3-dioxolane), 4-(1,3-dioxolane), 5-(1,3-dioxolane),tetrahydropyrane, (2-tetra hydropyrane, 3-tetrahydropyrane,4-tetrahydropyrane, 5-tetrahydropyrane, 6-tetrahydropyrane),hexahydropyridazine (1-(hexahydropyridazine), 2-(hexahydropyridazine),3-(hexahydropyridazine), 4-(hexahydropyridazine),5-(hexahydropyridazine), 6-(hexahydropyridazine)).

The term “aryl” as used herein includes carbocyclic aromatic ringsystems. Aryl is also intended to include the partially hydrogenatedderivatives of the carbocyclic systems.

The term “heteroaryl” as used herein includes heterocyclic unsaturatedring systems containing one or more heteroatoms selected from nitrogen,oxygen and sulphur such as furyl, thienyl, pyrrolyl, heteroaryl is alsointended to include the partially hydrogenated derivatives of theheterocyclic systems enumerated below.

The terms “aryl” and “heteroaryl” as used herein refers to an aryl whichcan be optionally substituted or a heteroaryl which can be optionallysubstituted and includes phenyl, biphenyl, indenyl, naphthyl(1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl,N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl,3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl,3-furyl), indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl,xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl(2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl(1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl).

The term “halogen” as used herein refers to fluoro, chloro, bromo, andiodo.

The term “aryl-C₁-C₅ alkyl” as used herein refers to an “aryl” group asdefined above attached through an “alkyl” group as defined above havingthe indicated number of carbon atoms.

The term “heteroaryl-C₁-C₅ alkyl” as used herein refers to a“heteroaryl” group as defined above attached through an “alkyl” group asdefined above having the indicated number of carbon atoms.

The term “C₃-C₇ cycloalkyl-C₁-C₅ alkyl” as used herein refers to a“cycloalkyl” group as defined above having the indicated number ofcarbon atoms attached through an “alkyl” group as defined above havingthe indicated number of carbon atoms.

The term “C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl” as used herein refers to a“cycloheteroalkyl” group as defined above having the indicated number ofcarbon atoms attached through an “alkyl” group as defined above havingthe indicated number of carbon atoms.

DESCRIPTION OF THE INVENTION

The present invention provides compounds of formula I

wherein A may be attached at either N¹ or at N² to the purine system and

-   each n and m is one or two independently-   R¹ is aryl optionally substituted with one or more R² independently    or heteroaryl optionally substituted with one or more R²    independently,-   R² is H, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloheteroalkyl, —NHCOR³, —NHSO₂R³, —SR³, —SOR³,    —SO₂R³, —OCOR³, —CO₂R⁴, —CON(R⁴)₂, —CSN(R⁴)₂, —NHCON(R⁴)₂,    —NHCSN(R⁴)₂, —NHCONNH₂, —SO₂N(R⁴)₂, —OR⁴, cyano, nitro, halogen,    wherein each alkyl, alkenyl, alkynyl, cycloalkyl and    cycloheteroalkyl is optionally substituted with one or more R³    independently,-   R³ is Halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, aryl, heteroaryl, —OR¹¹, —N(R¹¹)₂, —SR¹¹, wherein each    alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is    substituted with one or more R¹¹ independently,-   R⁴ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, aryl-C₁-C₅ alkyl,    heteroaryl, heteroaryl-C₁-C₅ alkyl, wherein each alkyl, alkenyl,    alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅ alkyl,    heteroaryl, and heteroaryl-C₁-C₅ alkyl is substituted with one or    more R¹¹ independently,-   R⁵ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloalkyl-C₁-C₅ alkyl, C₃-C₇ cycloheteroalkyl,    C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl, heteroaryl, aryl-C₁-C₅    alkyl, heteroaryl-C₁-C₅ alkyl, —OR⁷, —[(CH₂)_(n)—O]_(p)-alkyl,    wherein o and p are 1-3 independently, and wherein each alkyl,    alkenyl, alkynyl, cycloalkyl, cycloalkyl-C₁-C₅ alkyl,    cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl,    aryl-C₁-C₅ alkyl, heteroaryl, and heteroaryl-C₁-C₅ alkyl is    optionally substituted with one or more substituents independently    selected from R⁷ or R¹¹ independently,-   R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, aryl-C₁-C₅    alkyl, heteroaryl-C₁-C₅ alkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl,    wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl,    C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl, aryl-C₁-C₅ alkyl,    heteroaryl, aryl-C₁-C₅ alkyl, and heteroaryl-C₁-C₅ alkyl is    optionally substituted with one or more R¹¹ independently,-   R⁷ is H, ═O, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, —OR¹¹,    —N(R¹¹)₂, —SR¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,    cycloheteroalkyl, aryl, and heteroaryl is optionally substituted    with one or more R¹¹ independently,-   R⁸ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇    cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, —OR¹¹,    —N(R¹¹)₂, —SR¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl,    cycloheteroalkyl, aryl, and heteroaryl is optionally substituted    with one or more R¹¹ independently,-   R⁹ and R¹⁰ is independently H, C₁-C₁₀ alkyl optionally substituted    with one or more R⁸ independently, or halogen,-   R¹¹ is H, —CF₃, —CCl₃, —OCF₃, —OMe, cyano, halogen, —OH, —COMe,    —CONH₂, —CONHMe, —CONMe₂, —NO₂, C₁-C₁₀ alkyl, aryl, heteroaryl,    C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each alkyl,    cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally    substituted with one or more R¹² independently,-   R¹² is H, C₁-C₁₀ alkyl, —CF₃, —CCl₃, —OCF₃, —OMe, cyano, halogen,    —OH, —COMe, —CONH₂, —CONHMe, —CONMe₂, —NH₂, —NO₂-   If R⁹ and R¹⁰ is C₁-C₁₀ alkyl they may be connected to form a    cyclopropyl ring, if two R⁴ or two R¹¹ are attached to the same    nitrogen they may be connected to form a 3-to 7-membered ring,-   or any tautomeric form or any optical isomer or mixture of optical    isomers, including a racemic mixture, or a salt thereof with a    pharmaceutically acceptable acid or base.

In a further embodiment of the invention R¹ is aryl optionallysubstituted with one or more R² independently.

In a further embodiment of the invention R¹ is phenyl substituted withone or more R² independently.

In a further embodiment of the invention R¹ is aryl.

In a further embodiment of the invention R¹ is phenyl.

In a further embodiment of the invention R² is C₁-C₇ alkyl, C₂-C₇alkynyl, cyano, or halogen, wherein each alkyl and alkynyl is optionallysubstituted with one or more R³ independently.

In a further embodiment of the invention R² is C₁-C₇ alkyl, C₂-C₇alkynyl, cyano, or halogen.

In a further embodiment of the invention R² is methyl.

In a further embodiment of the invention R² is cyano or halogen.

In a further embodiment of the invention R³ is C₁-C₁₀ alkyl or aryl,wherein each alkyl or aryl is substituted with one or more R¹¹independently.

In a further embodiment of the invention R³ is C₁-C₁₀ alkyl or aryl.

In a further embodiment of the invention R³ is methyl or phenyl.

In a further embodiment of the invention R⁴ is H, C₁-C₁₀ alkyl or aryl,wherein each alkyl or aryl is substituted with one or more R¹¹independently.

In a further embodiment of the invention R⁴ is H, C₁-C₁₀ alkyl or aryl.

In a further embodiment of the invention R⁴ is H, methyl or phenyl.

In a further embodiment of the invention R⁵ is H, C₁-C₁₀ alkyl,aryl-C₁-C₅ alkyl, or heteroaryl-C₁-C₅ alkyl, wherein each alkyl,aryl-C₁-C₅ alkyl and heteroaryl-C₁-C₅ alkyl is optionally substitutedwith one or more R⁷ independently.

In a further embodiment of the invention R⁵ is H or C₁-C₁₀ alkyloptionally substituted with one or more R⁷ independently.

In a further embodiment of the invention R⁵ is H or C₁-C₁₀ alkyl.

In a further embodiment of the invention R⁵ is H.

In a further embodiment of the invention R⁵ is methyl.

In a further embodiment of the invention R⁶ is C₁-C₁₀ alkyl, aryl-C₁-C₅alkyl, or heteroaryl-C₁-C₅ alkyl, wherein each alkyl, aryl-C₁-C₅ alkyland heteroaryl-C₁-C₅ alkyl is optionally substituted with one or moreR¹¹ independently.

In a further embodiment of the invention R⁶ is C₁-C₁₀ alkyl, aryl-C₁-C₅alkyl, or heteroaryl-C₁-C₅ alkyl.

In a further embodiment of the invention R⁶ is C₁-C₁₀ alkyl optionallysubstituted with one or more R¹¹ independently.

In a further embodiment of the invention R⁶ is C₁-C₁₀ alkyl.

In a further embodiment of the invention R⁶ is methyl.

In a further embodiment of the invention R⁷ is H, ═O, aryl, heteroaryl,OR¹¹, N(R¹¹)₂, SR¹¹, wherein each aryl and heteroaryl is optionallysubstituted with one or more R¹¹ independently.

In a further embodiment of the invention R⁷ is H, ═O, aryl, orheteroaryl.

In a further embodiment of the invention R⁷ is H, ═O, OR¹¹, N(R¹¹)₂, orSR¹¹.

In a further embodiment of the invention R⁷ is H or ═O.

In a further embodiment of the invention R⁸ is aryl or heteroaryl,wherein each aryl and heteroaryl is optionally substituted with one ormore R¹¹ independently.

In a further embodiment of the invention R⁸ is aryl or heteroaryl.

In a further embodiment of the invention R⁸ is phenyl.

In a further embodiment of the invention R⁹ is H, C₁-C₁₀ alkyl, orhalogen.

In a further embodiment of the invention R⁹ is H.

In a further embodiment of the invention R¹⁰ is H, C₁-C₁₀ alkyl, orhalogen.

In a further embodiment of the invention R¹⁰ is H.

In a further embodiment of the invention R¹¹ is H, —CF₃, cyano, halogen,—OH, —NO₂, C₁-C₁₀ alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl,aryl, and heteroaryl is optionally substituted with one or more R¹²independently.

In a further embodiment of the invention R¹¹ is H, halogen, —OH, C₁-C₁₀alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl,wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroarylis optionally substituted with one or more R¹² independently.

In a further embodiment of the invention R¹¹ is H, halogen, —CH₃, aryl,heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein eachalkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R¹² independently.

In a further embodiment of the invention R¹¹ is H, halogen, —CH₃,heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein eachalkyl, cycloalkyl, cycloheteroalkyl, and heteroaryl is optionallysubstituted with one or more R¹² independently.

In a further embodiment of the invention R¹¹ is H, halogen, or —CH₃.

In a further embodiment of the invention R¹¹ is heteroaryl, C₃-C₇cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each cycloalkyl,cycloheteroalkyl, and heteroaryl is optionally substituted with one ormore R¹² independently.

In a further embodiment of the invention R¹¹ is selected from the groupconsisting of pyridine, cyclopentane, cyclohexane, and pyrrolidine,wherein each cycloalkyl, cycloheteroalkyl, and heteroaryl is optionallysubstituted with one or more R¹² independently In a further embodimentof the invention R¹² is H, C₁-C₁₀ alkyl, —CF₃, cyano, halogen, —OH,—COMe, —NH₂, —NO₂.

In a further embodiment of the invention R¹² is H, —CF₃, cyano, halogen,—OH, —NH₂.

In a further embodiment of the invention R¹² is —OH or —NH₂.

In a further embodiment of the invention n is two.

In a further embodiment of the invention n is one.

In a further embodiment of the invention m is two or three.

In a further embodiment of the invention m is two.

In a further embodiment of the invention m is three.

The following compounds are preferred:

-   2-(8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.    TFA-   8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   (S)    8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.    HCl-   8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   8-(3-Aminoazepan-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    TFA-   (S)    8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   (S)    2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.    HCl-   8-(3-Aminopiperidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    TFA-   (R)    8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.-   TFA-   (S)    8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.-   HCl-   (R)    8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   (R)    2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.    HCl-   (R)    8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   (R)    2-[8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]-benzonitrile.    HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    HCl-   (R)    8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.-   HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.-   HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.-   HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione.    TFA-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.    TFA-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.    TFA-   (R)    2-[8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile-   2-[8-(3-Aminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile-   (R)    2-[8-(3-Aminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile.    TFA-   (R)    2-[8-(3-(R)-Aminopiperidin-1-yl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.    HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.    HCl-   (R)    8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydropurine-2,6-dione.    HCl-   (R)    2-[8-(3-Aminopiperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-thiophen-3-yl-ethyl)-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.    TFA-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(3-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-chloro-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-bromo-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3,7-dibenzyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(3,5-difluoro-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2,5-difluoro-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-difluoromethoxy-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(3-fluoro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-methyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(3,5-difluoro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(3-fluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-1,3-dimethyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(3,5-difluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2,5-difluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-difluoromethoxy-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione-   8-(R-3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione-   2-[8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-7-(2-trifluoromethyl-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-1-(2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-7-(2-chloro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-(2-cyclopropyl-2-oxo-ethyl)-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(4-chloro-phenyl)-2-oxo-ethyl]-3-methyl--   3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-p-tolyl-ethyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2-chloro-phenyl)-2-oxo-ethyl]-3-methyl--   3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-butyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(3-chloro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   2-{8-(3-Amino-piperidin-1-yl)-1-[2-(2,6-difluoro-phenyl)-2-oxo-ethyl]-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl}-benzonitrile-   2-[8-(3-Amino-piperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-thiophen-3-yl-ethyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile-   2-[8-(3-Amino-piperidin-1-yl)-1-(2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile-   2-[8-(3-Amino-piperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-phenyl-ethyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile-   2-{8-(3-Amino-piperidin-1-yl)-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl}-benzonitrile-   8-(3-Amino-piperidin-1-yl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-7-(3-trifluoromethoxy-benzyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-fluoro-6-trifluoromethyl-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione-   8-(3-Amino-piperidin-1-yl)-7-(2-fluoro-5-trifluoromethyl-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione-   2-(8-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile.    TFA-   8-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Aminoazepan-1-yl)-7-benzyl-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Aminoazepan-1-yl)-7-benzyl-3-methyl-3,7-dihydropurine-2,6-dione.    TFA-   2-(8-(3-Aminoazepan-1-yl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.    TFA-   8-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Aminoazepan-1-yl)-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione.-   TFA-   8-(3-Aminoazepan-1-yl)-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.    TFA-   2-[8-(3-Aminoazepan-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.    TFA-   8-(3-Aminoazepan-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.    TFA-   8-(3-Amino-azepan-1-yl)-7-(2-chloro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione,    TFA-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclohexyl-acetamide-   (R)    8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-3,7-dihydro-purine-2,6-dione-   (R)    2-[8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclopentylacetamide.    TFA-   2-[8-(3-(R)    Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(1-aza-bicyclo[2.2.2]oct-3-yl)-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide-   (R,R)    8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-1-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide-   (R) 2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,    3,6,7-tetrahydro-purin-1-yl]-N-cyclohexyl-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclopentyl-acetamide-   2-[8-(3-(R)-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(1-aza-bicyclo[2.2.2]oct-3-yl)-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-3-yl-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(6-amino-pyridin-2-yl)-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide-   (R)    2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide-   (R)    8-(3-Amino-piperidin-1-yl)-1,3-dimethyl-7-thiophen-2-ylmethyl-3,7-dihydro-purine-2,6-dione

The compounds of the present invention may be chiral, and it is intendedthat any enantiomers, as separated, pure or partially purifiedenantiomers or racemic mixtures thereof are included within the scope ofthe invention.

Furthermore, when a double bond or a fully or partially saturated ringsystem or more than one centre of asymmetry or a bond with restrictedrotatability is present in the molecule diastereomers may be formed. Itis intended that any diastereomers, as separated, pure or partiallypurified diastereomers or mixtures thereof are included within the scopeof the invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric forms,which the compounds are able to form, are included within the scope ofthe present invention.

Compounds of formula I may be used for the manufacture of a medicamentfor treating diseases associated with proteins that are subject toinactivation by DPP-IV.

A further aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treating a conditionthat may be regulated or normalised via inhibition of DPP-IV.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of metabolicdisorders.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for blood glucoselowering.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of Type 2diabetes Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired glucose tolerance (IGT).

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofimpaired fasting glucose (IFG).

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for prevention ofhyperglycemia.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of impaired glucose tolerance (IGT) to Type 2 diabetes.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for delaying theprogression of non-insulin requiring Type 2 diabetes to insulinrequiring Type 2 diabetes.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for increasing the numberand/or the size of beta cells in a mammalian subject.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment of beta celldegeneration, in particular apoptosis of beta cells.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdisorders of food intake.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofobesity.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for appetite regulation orinduction of satiety.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for the treatment ofdyslipidemia.

Another aspect of the invention is the use of a compound of theinvention for the manufacture of a medicament for treatment offunctional dyspepsia, in particular irritable bowel syndrome.

A further aspect of the invention is a method for treating theconditions mentioned above by administering to a subject in need thereofan effective amount of a compound of the invention.

The compounds of the present invention may be prepared in the form ofpharmaceutically acceptable salts, especially acid-addition salts,including salts of organic acids and mineral acids. Examples of suchsalts include salts of organic acids such as formic acid, fumaric acid,acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid,oxalic acid, succinic acid, malic acid, tartaric acid, citric acid,benzoic acid, salicylic acid and the like. Suitable inorganicacid-addition salts include salts of hydrochloric, hydrobromic,sulphuric and phosphoric acids and the like. Further examples ofpharmaceutically acceptable inorganic or organic acid addition saltsinclude the pharmaceutically acceptable salts listed in Journal ofPharmaceutical Science, 66, 2 (1977) that are known to the skilledartisan.

Also intended as pharmaceutically acceptable acid addition salts are thehydrates that the present compounds are able to form.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent.

The compounds of this invention may form solvates with standard lowmolecular weight solvents using methods known to the skilled artisan.

It is to be understood that the invention extends to all of the stereoisomeric forms of the claimed compounds, as well as the racemates.

Pharmaceutical Compositions

In another aspect, the present invention includes within its scopepharmaceutical compositions comprising, as an active ingredient, atleast one compound of the invention which inhibits the enzymaticactivity of DPP-IV or a pharmaceutically acceptable salt or prodrug orhydrate thereof together with a pharmaceutically acceptable carrier ordiluent.

Pharmaceutical compositions containing a compound of the invention ofthe present invention may be prepared by conventional techniques, e.g.as described in Remington: The Science and Practise of Pharmacy, 19^(th)Ed., 1995. The compositions may appear in conventional forms, forexample capsules, tablets, aerosols, solutions, suspensions or topicalapplications.

Typical compositions include a compound of the invention which inhibitsthe enzymatic activity of DPP-IV or a pharmaceutically acceptable basicaddition salt or prodrug or hydrate thereof, associated with apharmaceutically acceptable excipient which may be a carrier or adiluent or be diluted by a carrier, or enclosed within a carrier whichcan be in the form of a capsule, sachet, paper or other container. Inmaking the compositions, conventional techniques for the preparation ofpharmaceutical compositions may be used. For example, the activecompound will usually be mixed with a carrier, or diluted by a carrier,or enclosed within a carrier which may be in the form of a ampoule,capsule, sachet, paper, or other container. When the carrier serves as adiluent, it may be solid, semi-solid, or liquid material which acts as avehicle, excipient, or medium for the active compound. The activecompound can be adsorbed on a granular solid container for example in asachet. Some examples of suitable carriers are water, salt solutions,alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil,peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, dextrin,magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate,talc, gelatine, agar, pectin, acacia, stearic acid or lower alkyl ethersof cellulose, silicic acid, fatty acids, fatty acid amines, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.Similarly, the carrier or diluent may include any sustained releasematerial known in the art, such as glyceryl monostearate or glyceryldistearate, alone or mixed with a wax. The formulations may also includewetting agents, emulsifying and suspending agents, preserving agents,sweetening agents or flavouring agents. The formulations of theinvention may be formulated so as to provide quick, sustained, ordelayed release of the active ingredient after administration to thepatient by employing procedures well known in the art.

The pharmaceutical compositions can be sterilized and mixed, if desired,with auxiliary agents, emulsifiers, salt for influencing osmoticpressure, buffers and/or colouring substances and the like, which do notdeleteriously react with the active compounds.

The route of administration may be any route, which effectivelytransports the active compound of the invention which inhibits theenzymatic activity of DPP-IV to the appropriate or desired site ofaction, such as oral, nasal, pulmonary, buccal, subdermal, intradermal,transdermal or parenteral e.g. rectal, depot, subcutaneous, intravenous,intraurethral, intramuscular, intranasal, ophthalmic solution or anointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation maybe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation may be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

For nasal administration, the preparation may contain a compound of theinvention which inhibits the enzymatic activity of DPP-IV, dissolved orsuspended in a liquid carrier, in particular an aqueous carrier, foraerosol application. The carrier may contain additives such assolubilizing agents, e.g. propylene glycol, surfactants, absorptionenhancers such as lecithin (phosphatidylcholine) or cyclodextrin, orpreservatives such as parabenes.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Tablets, dragees, or capsules having talc and/or a carbohydrate carrieror binder or the like are particularly suitable for oral application.Preferable carriers for tablets, dragees, or capsules include lactose,corn starch, and/or potato starch. A syrup or elixir can be used incases where a sweetened vehicle can be employed.

A typical tablet which may be prepared by conventional tablettingtechniques may contain: Core: Active compound (as free compound or saltthereof) 250 mg Colloidal silicon dioxide (Aerosil) ®  1.5 mg Cellulose,microcryst. (Avicel) ®  70 mg Modified cellulose gum (Ac-Di-Sol) ®  7.5mg Magnesium stearate Ad. Coating: HPMC approx.  9 mg *Mywacett 9-40 Tapprox.  0.9 mg*Acylated monoglyceride used as plasticizer for film coating.

The compounds of the invention are effective over a wide dosage range.For example, in the treatment of adult humans, dosages from about 0.05to about 1000 mg, preferably from about 0.1 to about 500 mg, per day maybe used. A most preferable dosage is about 0.5 mg to about 250 mg perday. In choosing a regimen for patients it may frequently be necessaryto begin with a higher dosage and when the condition is under control toreduce the dosage. The exact dosage will depend upon the mode ofadministration, on the therapy desired, form in which administered, thesubject to be treated and the body weight of the subject to be treated,and the preference and experience of the physician or veterinarian incharge.

Generally, the compounds of the present invention are dispensed in unitdosage form comprising from about 0.05 to about 1000 mg of activeingredient together with a pharmaceutically acceptable carrier per unitdosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermaladministration comprise from about 0.05 mg to about 1000 mg, preferablyfrom about 0.5 mg to about 250 mg of the compounds admixed with apharmaceutically acceptable carrier or diluent.

The invention also encompasses prodrugs of a compound of the inventionwhich on administration undergo chemical conversion by metabolicprocesses before becoming active pharmacological substances. In general,such prodrugs will be functional derivatives of a compound af theinvention which are readily convertible in vivo into a compound af theinvention. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs”, ed. H. Bundgaard, Elsevier, 1985.

Combination Treatments

The invention furthermore relates to the use of a compound according tothe present invention for the preparation of a medicament for use in thetreatment of diabetes in a regimen which additionally comprisestreatment with another antidiabetic agent.

In the present context the expression “antidiabetic agent” includescompounds for the treatment and/or prophylaxis of insulin resistance anddiseases wherein insulin resistance is the pathophysiological mechanism.

In one embodiment of this invention, the antidiabetic agent is insulinor GLP-1 or any analogue or derivative thereof.

In another embodiment the antidiabetic agent is a hypoglycaemic agent,preferably an oral hypoglycaemic agent.

Oral hypoglycaemic agents are preferably selected from the groupconsisting of sulfonylureas, non-sulphonylurea insulin secretagogues,biguanides, thiazolidinediones, alpha glucosidase inhibitors, glucagonantagonists, GLP-1 agonists, potasium channel openers, insulinsensitizers, hepatic enzyme inhibitors, glucose uptake modulators,compounds modifying the lipid metabolism, compounds lowering foodintake, and agents acting on the ATP-dependent potassium channel of theβ-cells.

Among the sulfonylureas, tolbutamide, glibenclamide, glipizide andgliclazide are preferred.

Among the non-sulphonylurea insulin secretagogues, repaglinide andnateglinide are preferred.

Among the biguanides, mefformin is preferred.

Among the thiazolidinediones, troglitazone, rosiglitazone andciglitazone are preferred.

Among the glucosidase inhibitors, acarbose is preferred.

Among the agents acting on the ATP-dependent potassium channel of theβ-cells the following are preferred: glibenclamide, glipizide,gliclazide, repaglinide.

The cyclic amines used in the synthesis of the compounds of theinvention are either commercially available, or have been made usingpublished procedures. Racemic 3-aminopiperidine was made from3-aminopyridine by reduction with PtO₂ (Nienburg. Chem. Ber.70(1937)635). Enantiopure (R)- and (S)-3-aminopiperidine and (R)- and(S)-3-Aminopyrrolidine was made according to Moon, S-H and Lee, S.Synth. Commun. 28(1998)3919.

Pharmacological Methods

Methods for Measuring the Activity of Compounds which Inhibit theEnzymatic Activity of CD26/DPP-IV

SUMMARY

Chemical compounds are tested for their ability to inhibit the enzymeactivity of purified CD26/DPP-IV. Briefly, the activity of CD26/DPP-IVis measured in vitro by its ability to cleave the synthetic substrateGly-Pro-p-nitroanilide (Gly-Pro-pNA). Cleavage of Gly-Pro-pNA by DPP-IVliberates the product p-nitroanilide (pNA), whose rate of appearance isdirectly proportional to the enzyme activity. Inhibition of the enzymeactivity by specific enzyme inhibitors slows down the generation of pNA.Stronger interaction between an inhibitor and the enzyme results in aslower rate of generation of pNA. Thus, the degree of inhibition of therate of accumulation of pNA is a direct measure of the strength ofenzyme inhibition. The accumulation of pNA is measuredspectrophotometrically. The inhibition constant, Ki, for each compoundis determined by incubating fixed amounts of enzyme with severaldifferent concentrations of inhibitor and substrate.

Materials:

The following reagents and cells are commercially available:

-   Porcine CD26/DPP-IV (Sigma D-7052), Gly-Pro-pNA (Sigma G0513).-   Assay buffer: 50 mM Tris pH 7.4, 150 mM NaCl, 0,1% Triton X-100.    Gly-Pro-pNA cleavage-assay for CD26:

The activity of purified CD26/DPP-IV is assayed in reactions containing:

-   70 μl assay buffer-   10 μl inhibitor or buffer-   10 μl substrate (Gly-Pro-pNA from a 0.1 M stock solution in water)    or buffer-   10 μl enzyme or buffer

Reactions containing identical amounts of enzyme, but varyingconcentrations of inhibitor and substrate, or buffer as control, are setup in parallel in individual wells of a 96-well ELISA plate. The plateis incubated at 25° C. and absorbance is read at 405 nm after 60 minincubation. The inhibitor constants are calculated by non-linearregression hyperbolic fit and the result is expressed as inhibitionconstant (Ki) in nM.

Diabetes Model

The Zucker Diabetic Fatty (ZDF) rat model can be used to investigate theeffects of the compounds of the invention on both the treatment andprevention of diabetes as rats of this sub-strain are initiallypre-diabetic although develop severe type 2 diabetes characterised byincreased HbA1c levels over a period of 6 weeks. The same strain can beused to predict the clinical efficacy of other anti-diabetic drug types.For example, the model predicts the potency and limited clinicalefficacy of thiazolidinedione insulin sensitizers compounds.

EXAMPLES

Preparative HPLC (Method A1)

Column: 1.9×15 cm Waters XTerra RP-18. Buffer: linear gradient 5-95% in15 min, MeCN, 0.1% TFA, flow rate of 15 ml/min. The pooled fractions areeither evaporated to dryness in vacuo, or evaporated in vacuo until theMeCN is removed, and then frozen and freeze dried.

Preparative HPLC (Method A2) D9.1.19

Column: Supelcosil ABZ+Plus, 25 cm×10 mm, 5 μm. Solvent A: 0.1%TFA/Water, solvent B: MeCN. Eluent composition: 5 min. 100% A, lineargradient 0-100% B in 7 min, 100% B in 2 min. Flow rate 5 ml/min. Thecolumn is allowed to equilibrate for 4 min in 100% A before the nextrun.

Preparative HPLC (Method A3) HDemPrep

The LC system consists of a Gilson 321 pump, 235 injector and215-fraction collector equipped with a Waters Xterra 7.8 mm*100 mmcolumn run with a gradient from 10% aqueous acetonitril with 0.01% TFAto 100% acetonitril with 0.01% TFA over 11 min. Flow rate 10 ml/min. Theeffluent is split 1:1000 to an Agilent 1100 MSD by a LC Packings ACM10-50 flow splitter. The MS is equipped with an Agilent fractioncollector kit, from which the analogue signal from extracted the targetion, is used for controlling fraction collection.

HPLC-MS (Method B) (Anyone)

Column: Waters Xterra MS C-18×3 mm id. Buffer: Linear gradient 10-100%in 7.5 min, MeCN, 0.01% TFA, flow rate 1.0 ml/min. Detection 210 nm(analog output from diode array detector), MS-detection ionisation modeAPI-ES, scan 100-1000 amu step 0.1 amu.

HPLC-MS (Method C) (h8)

Column: 0.3 mm×15 cm Waters Symmetry C₁₈. Buffer: Linear gradient 5-90%in 15 min, MeCN, 0.05% TFA, flow rate 1 ml/min

Analytical Separation of Stereoisomers (Method D)

CCE, Chiral capillary electrophoresis: Conditions: HP 3D CapillaryElectrophoresis: 48.5/40 cm, 50 μm HP bubble capillary, Electrolyte:HS-β-CD (Regis) (2% w/v) in 50 mM phosphate buffer pH2.5 (HP), Voltage:−17 kV, Injection: 30 mbar for 5s.

Preparative Separation of Stereoisomers (Method E)

Analytical separations were performed on Hewlett Packard 1090 HPLCequipment with 5 chiral Daicel columns (AD, OD, AS, OJ and Welko-O2,250×4.6 mm) with a diode array detector. The mobile phases were2-propanol:heptane mixtures with 0.1% DEA.

Preparative separations were performed with the above-mentioned type ofcolumns (250×20 mm) on a preparative Gilson HPLC set-up. Relevantfractions were collected and evaporated (SpeedVac).

Microwave Assisted Reactions (Method F)

The reactants are mixed in an appropriate solvent in a closed teflonvessel (XP 1500 Plus Vessel set) and heated in a micro wave oven (CEMMARSX microwave instrument. Magnetron frequency: 2455 MHz. Power Output:1200 Watt.). The reaction mixture is cooled and evaporated in vacuo.Normally solvents like MeOH, EtOH, iPrOH, H₂O, DMF and DMSO are used.

Chiral Capillary Electrophoresis (CCE) Analysis of 3-aminopiperidine(Method G)

The chiral analysis of 3-aminopiperidine consists of a derivatisationstep prior to chiral analysis using capillary electrophoresis (CE).

Derivatisation, 50 μl 40 mM 3-aminopiperidine solution in water is addedto 200 μl 40 mM OPA solution (40 mM OPA in 1:15:185mercaptaethanol:MeOH:water). The reaction in carried out in the darkwithin 2 minutes. 50 μl of this reaction mixture is diluted with 950 μlwater and analysed directly on the CE instrument.

CE instrumentation and conditions, HP^(3D)CE instrument equipped with a48.5/40.0 cm bubble cell capillary and detection at 226 nm UV. Theinjection was 50 mbar in 4.0 seconds. The applied voltage was +19 kVwhich yielded +60 μA and prior to each injection the capillary waswashed with 0.1N NaOH for 1 minute and electrolyte for 1.5 minutes. Theelectrolyte was 0.5% (w/v) carboxyethyl-β-cyclodextrin (Cyclolab,Hungary) dissolved in 50 mM fosphate buffer pH 7.0. The two enantiomersmigrate within 5 minutes of electrophoresis and the identity of specificenantiomers is confirmed by spiking of the racemate.

Preparation of (R) piperidine-3-ylamine

Step A: (R)N-CBz Nipecotic Acid

R (−) Ethylnipeconate tartaric acid salt (117 g, 382 mmol) was dissolvedin 2N NaOH (1200 ml, 2.40 mol) and cooled to 5° C. Z-OSu (100 g, 401mmol) dissolved in 100 ml THF was added to the chilled reaction. Themixture was allowed to stir at 5° C. for 1 h. and at RT overnight.Approx. 100 ml of solvent was removed by rotary evaporation in vacuo,and the remaining solution was acidified to pH 2-3 with conc. HCl (app.75 ml). The resulting crystal were isolated by filtration and dried invacuo overnight.

Yield 86 g (85%)

¹H-NMR (dmso-d6, 400 MHz) δ. 12.5 (s broad, 1H), (7.42-7.30 (m, 5H), 5.1(s, 2H), 4.0 (s, 1H), 3.80 (s, 1H), 3.12 (m, 1H), 2.92 (t, 1H), 2.36 (m,1H), 1.92 (m, 1H), 1.7-1.48 (m, 2H), 1.48-1.30 (m, 1H). HPLC-MS (MethodB): m/z=264 (M+1), R_(t)=3.30 min.

Step B: (R) 3-tert-Butoxycarbonylamino-piperidine-1-carboxylic AcidBenzyl Ester

(R)N-CBz nipecotic acid (86 g, 327 mmol) was dissolved in toluene (100ml) and evaporated to dryness three times. tert. Butanol (1000 ml, 10.5mmol) and triethylamine (50.1 ml, 359 mmol) were added to the reactionmixture. The reaction mixture was stirred for 30 min., and DPPA (98.5ml, 457 mmol) was added over 15 min. The reaction mixture was heated to100° C. overnight. After cooling, the solvent was removed by evaporationin vacuo, and water (200 ml) was added. After overnight stirring at RTthe product was isolated by filtration, and stirred with EtOAc (250 ml)for one hour. The EtOAc solution was filtered and evaporated in vacuo togive the crude product as a white solid. This material was dissolved inhot EtOAc (200 ml), and cooled to 5° C. overnight. The precipitatedproduct was isolated by filtration, washed with cold EtOAc and dried.

Yield 50.0 g (46%).

¹H-NMR (dmso-d6, 400 MHz) δ: 7.32 (s, 5H), 5.12 (s, 2H), 4.6 (s, 1H),3.8-3.15 (m, 5H), 1.85 (m, 1H), 1.65 (s, 1H), 1.6-1.35 (m, 11H).

Step C: (R) Piperidin-3-yl-carbamic Acid Tert.-Butyl Ester

(R) 3-tert-Butoxycarbonylamino-piperidine-1-carboxylic acid benzyl ester(50 g, 150 mmol) was dissolved in abs. EtOH (500 ml), and hydrogenated(1 atm, 7 days, 10% Pd/C (5.0 g)) at RT. The reaction was filtered andevaporated in vacuo to give the product as a white solid

Yield 27.3 g (92%).

¹H-NMR (dmso-d6, 300 MHz) δ: 6.85 (d, 1H), 3.41 (s br, 2H), 3.05 (m,1H), 2.90 (m, 1H), 2.58-2.35 (m, 2H), 1.92 (m, 1H), 1.75 (m, 1H), 1.58(s, 9H), 1.50-1.40 (m, 2H).

For analysis a small sample of the product (50 mg) was dissolved inEtOAc (2 ml), treated with 3 N HCl in EtOAc (2 ml), and evaporated invacuo. The product was stirred with EtOAc (5 ml) for one hour andfiltered to give (R) 3-aminopiperidine in >98% ee, (determined asdescribed in method G).

Preparation of Azepan-3-ylamine

3-Amino-azepan-2-one (24,0 g, 0,188 mol) was dissolved in THF and cooledon an ice bath in a nitrogen atmosphere. LiAlH₄ (35,6 g, 0.938 mol) wasadded in small portions. After the last addition the re-action mixturewas allowed to warm up to room temperature and stirred for 72 hours,then refluxed for 48 hours. Water was added very slowly until a whitereaction mixture was obtained. K₂CO₃ was added until a filterable slurrywas obtained. Then the reaction mixture was filtered, and theprecipitate was washed with THF (3×300 ml). The combined THF phase wasevaporated in vacuo giving the title compound as a yellow oil. Nofurther purification was performed.

HPLC-MS: (Method B): m/z=115 (M+1), R t=0.53 min, Purity (UV)=99%.

¹H-NMR (MeOD-d₄): δ: 4.5 (s, 3H), 2.8-3.0 (m, 4H), 2.45-2.6 (m, 1H), 1.9(m, 1H), 1.4-1.75 (m, 5H).

¹³C-NMR (MeOD-d₄): δ: 57.68, 54.40, 50.19, 38.04, 31.79, 24.01.Abbreviations CBz Carbobenzoxycarbonyl EtOAc Ethyl acetate DCMDichloromethane DEA Diethylamine DIEA Diisopropylethylamine DMFDimethylformamide DMSO Dimethyl sulfoxide DPPA Diphenylphosphonic azideHOAc Acetic acid MeCN Acetonitrile TFA Trifluoroacetic acid THFTetrahydrofuran TMG Tetramethylguanidine

General Procedure (A):

Step A:

The starting material (16 μmol) is dissolved in a mixture of DMF andDIEA (3% DIEA, 250 μl). The alkylation reagent R¹-CR⁹R⁹—X (16.8 μmol,1.05 equiv) is dissolved in DMF (100 μl) and added. The mixture isheated to 65° C. for 2 h.

Step B:

Alkylation reagent R⁵—Br (32 μmol) is dissolved in DMF (100 μl) andadded to the reaction mixture followed by a solution of TMG in DMF (1.16ml TMG diluted to 5.8 ml, 48 μl). The mixture is kept at 65° C. for 4 h.

Step C:

The diamine (200 μmol) is dissolved in a mixture of DMF and DIEA (3%DIEA, 200 μl) and added to the reaction mixture. The reaction is kept at50° C. for 24 h.

Samples are neutralized using HOAc (20 μl), stripped and purified byHPLC. Samples are dissolved in DMSO/H₂O (4:1, 500 μl).

General Procedure (B)

Step A:

The starting material (16 μmol) is dissolved in a mixture of DMF andDIEA (3% DIEA, 250 μl). The alkylation reagent R¹-CR⁹R⁹—X (16.8 μmol,1.05 equiv) is dissolved in DMF (100 μl) and added. The mixture isheated to 65° C. for 2 h.

Step B:

Diamine (200 μmol) is dissolved in a mixture of DMF and DIEA (3% DIEA,200 μl) and added to the reaction mixture. The reaction is kept at 50°C. for 24-48 h, and then all volatiles are stripped.

Samples are neutralized using HOAc (20 μl), stripped and purified byHPLC methods A1, A2 or A3. Samples are dissolved in DMSO/H₂O (4:1, 500μl).

General Procedure C

Step A:

8-Chlorotheophylline (1 eq.) and K₂CO₃ (2.2 eq) is slurried in DMF (app.12 ml/g of 8-Chlorotheophylline). The benzyl chloride (or bromide) isadded (1.1 eq), and the slurry is stirred until the reaction is finished(1-7 days) at RT. The reaction mixture is poured into water (app. 70ml/g 8-Chlorotheophylline) and stirred until the precipitation of theproduct has completed.

The product is filtered and dried in vacuo.

Step B:

The benzylated 8-Chlorotheophylline (1 eq.) is dissolved in DMSO (app.35 ml/g), K₂CO₃ (4 eq.) is added, and then (R) Piperidin-3-yl-carbamicacid tert.-butyl ester (2 eq.) is added, and the reaction is stirred ateither RT, 50° C., or at 65° C. until finished (usually overnight). Thereaction mixture is poured into water (4-10 ml/ml DMSO) with stirring,and the precipitated product is isolated by filtration, and washed withwater, and dried.

Step C:

The product from step B (1 eq.) is dissolved in MeCN (app. 20 ml/g), andconc. HCl is added (10 eq.). The reaction is left with stirringovernight, and evaporated in vacuo. The product is dissolved in EtOAcand water (1+1, app. 50 ml/g), separated, and the aqueous phase washedwith EtOAc (2×25 ml/g). The aqueous phase is added an equal amount of 2NK₂CO₃, and extracted with EtOAc (3×25 ml/g). The combined EtOAc phase iswashed with brine, dried (MgSO₄), and about half the solvent is removedby evaporation in vacuo.

Conc. HCl is added (1.1 eq.), and the solvent is evaporated in vacuo.The product is dissolved in hot EtOH, precipitated with Et₂O, collectedby filtration, and dried in vacuo.

General Procedure (D):

Step A:

The starting material (32 μmol) is dissolved in a mixture of DMF andDIEA (3% DIEA, 500 μl). The alkylation reagent R¹—CR⁹R⁹—X (33.6 μmol,1.05 equiv) is dissolved in DMF (200 μl) and added. The mixture isheated to 65° C. for 2 h. Upon cooling to 25° C., K₂CO₃ (aq) is added(5.12M, 50 μL, 256 umol). Volatiles are stripped.

Step B:

Alkylation reagent R⁵—Br (64 μmol) is dissolved in DMF (250 μl) andadded to the reaction mixture. The mixture is kept at 25° C. for 48 h.Volatiles are stripped.

Step C:

The diamine (400 μmol) is dissolved in DMSO and added to the reactionmixture. If the dihydrochloride salt of the diamine is employed, fourequivalents of DCHMA is added. The reaction is kept at 50° C. for 48 h.

Samples are neutralized using HOAc (30 μl), and purified by HPLC MethodA3.

General Procedure (E):

Step A:

The starting material (4.08 mmol) is dissolved in a mixture of DMF andDIEA (3% DIEA, 65 ml). The alkylation reagent R¹-CR⁹R⁹—X (4.28 mmol,1.05 equiv) is dissolved in DMF (25.5 ml) and added. The mixture isheated to 65° C. for 2 h and poured onto ice followed by filtration ofthe alkylated product.

Step B:

Diamine (400 μmol) is dissolved in DMSO (400 μl) and added to the aboveproduct (32 mmol). The reaction is kept at 50° C. for 24-48 h.

Samples are neutralized using HOAc (30 μl) and purified by HPLC MethodA1 or HPLC Method A2.

General Procedure (F):

Step A:

The starting material (32 μmol) is dissolved in a mixture of DMF andDIEA (3% DIEA, 500 μl). The alkylation reagent R¹-CR⁹R⁹—X (33.6 μmol,1.05 equiv) is dissolved in DMF (200 μl) and added. The mixture isheated to 65° C. for 2 h.

Step B:

Diamine (400 μmol) is dissolved in DMSO (400 μl) and added to the abovereaction mixture.

The reaction is kept at 50° C. for 48 h.

Samples are neutralized using HOAc (30 μl) and purified by HPLC MethodA2 or A3.

General Procedure (G):

Step A:

The starting material (20.40 mmol) is dissolved in DMF (50 ml) and DIEA(10 ml). The alkylation reagent R¹-CR⁹R⁹—X (22.03 mmol, 1.08 equiv) isdissolved in DMF (10 ml) and added. Heating the mixture to 65° C. for 2h affords the products that are isolated by filtration upon adding thereaction mixture onto ice (300 ml).

Step B:

The product from Step A (5.56 mmol) and alkylation reagent R⁵—Br (11.11mmol) are dissolved in DMF (60 ml) and potassium carbonate is added tothe reaction mixture. Upon stirring at 25° C. for 16 h the reactionmixture is poured onto ice (300 ml) and the product is isolated byfiltration and dried in vacuo.

Step C:

The product from Step B (0.472 mmol) is dissolved in DMSO (5 ml) and thediamine (2.36 mmol) is added to the reaction mixture. If thedihydrochloride salt of the diamine is employed, K₂CO₃ (2.36 mmol) isadded. The reaction is kept at 50° C. for 24 h and poured onto ice (20ml). The product is isolated by filtration. The compounds may bepurified by HPLC methods A1, A2 or A3 or by treatment with hotacetonitrile.

General Procedure (H):

Step A:

The starting material (20.40 mmol) is dissolved in DMF (50 ml) and DIEA(10 ml). The alkylation reagent R¹—CR⁹R⁹—X (22.03 mmol, 1.08 equiv) isdissolved in DMF (10 ml) and added. H eating the mixture to 65° C. for 2h affords the products that are isolated by filtration upon adding thereaction mixture onto ice (300 ml).

Step B:

The product from step A is dissolved in DMSO (app. 40 ml/g), DIEA (2eq.) is added, and then (R) Piperidin-3-yl-carbamic acid tert.-butylester (2 eq.) is added, and the reaction is stirred at either RT, 50°C., or at 65° C. until finished (usually overnight). The reactionmixture is poured into ice/water (4-10 ml/ml DMSO) with stirring, andthe precipitated product is isolated by filtration, and washed withwater, and dried.

Step C:

The product from step B is dissolved in DMF (1 eq. app. 10 ml/g). Ethyl2-bromoacetate is added (2 eq.) is added, K₂CO₃ (3.5 eq) is furtheradded, and the reaction is left with stirring at RT until completed. Thereaction is poured onto ice/water (app. 100 ml), and the precipitatedproduct is isolated by filtration, and washed with water, and dried.

Step D:

The product from step C is dissolved in EtOH (25 ml) with stirring,added 1 N NaOH (6 ml), and left with stirring overnight. HOAc (6 ml) isadded, and the solvent is evaporated. The residue is poured ontoice/water (app. 100 ml), and the precipitated product is isolated byfiltration, and washed with water, and dried.

Step E:

The product from step D (1 eq. 20 μmol) is dissolved in a solution ofCarbonyldiimidazole (1.5 eq. 30 μM) in DMF (250 μl), and left for 2hours. The amine NRR′ (2 eq. 40 μM), dissolved in DMF (50 μl), was addedand the reaction left with stirring overnight at RT.

Another portion of the amine was added as before, and the reaction leftwith stirring overnight. The product was isolated by evaporation of thesolvent.

Step F:

The product from step E was added TFA in DCM (200 μl 1:1), and thereaction was left for 2 hours. Evaporation of the solvent overnight gavethe product, which may be further purified by prep. HPLC methods A1, A2or A3.

NNC 0072-0000-1085

Example 12-(8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.TFA (1)

NNC 0072-0000-5060-Step A:2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(1A)

8-Chlorotheophylline (20 g, 93.19 mmol) was dissolved in 800 ml of DMFand 2-cyanobenzyl bromide (18.28 g, 93.19 mmol), potassium carbonate(12.88 g, 93.19 mmol), and potassium iodide (10 mg, 0.06 mmol) wereadded. The mixture was stirred at room temperature for 20 hours. Thesolvent was evaporated and the residue was suspended in 900 ml of waterand 900 ml of EtOAc, and compound (1A) was collected by filtration ofthe suspension. The layers in the mother liquor were separated and theaqueous layer was extracted with 3×500 ml of EtOAc. The combined organiclayers were washed with 1×500 ml of water, and the solvent wasevaporated to give compound (1A) as white crystals.

Combined yield: 28.6 g (93%). Mp. 222.5-223.7° C.

¹H-NMR (DMSO, 300 MHz) δ: 3.20 (s, 3H), 3.43 (s, 3H), 5.74 (s, 2H), 7.06(d, 1H), 7.53 (t, 1H), 7.67 (t, 1H), 7.93 (d, 1H). HPLC-MS (Method B):m/z=330 (M+1), R_(t)=2.93 min.

NNC 0072-0000-1085-Step B:2-(8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.TFA (1)

2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(1A) (100 mg, 0.30 mmol) and 3-aminopiperidine dihydrochloride (262 mg,1.52 mmol) were dissolved in 20 ml of 2-propanol and triethylamine(0.127 ml, 0.91 mmol) and subjected to microwaves (method F, 130° C.,300 W) for ten hours. The solvents were evaporated and the crude productwas purified by preparative HPLC, (method A1, R_(t)=6.78 min.) to givethe title compound as oily crystals.

Yield: 66 mg (43%).

¹H-NMR (MeOD, 300 MHz) δ: 1.73 (m, 3H), 2.10 (m, 1H), 3.02 (m, 1H), 3.20(m, 2H), 3.27 (s, 3H), 3.52 (m, 4H), 3.65 (m, 1H), 5.59 (s, 2H), 7.22(d, 1H), 7.47 (m, 1H), 7.61 (m, 1H), 7.78 (d, 1H). HPLC-MS (Method B):m/z=394 (M+1), R_(t)=1.55 min.

Example 28-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (2)

Step A: 7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A)

8-Chlorotheophylline (50 g, 0.23 mol) was suspended in 600 ml of DMF andbenzyl bromide (31 ml, 0.26 mol) and potassium carbonate (64 g, 0.46mol) were added. The mixture was stirred at room temperature for 20hours. The solvent was evaporated and the residue was dissolved in 250ml of water and 400 ml of DCM. The layers were separated and the aqueouslayer was extracted with 150 ml of DCM. The combined organic layer waswashed with 100 ml of brine, dried over magnesium sulphate, filtered,and the solvent was evaporated to give compound (2A) as white crystals.

Yield: 73.6 g (104%). Mp. 152-154° C.

¹H-NMR (CDCl₃, 200 MHz) δ: 3.42 (s, 3H), 3.55 (s, 3H), 5.55 (s, 2H),7.35 (m, 5H). HPLC-MS (Method B): m/z=305 (M+1), R_(t)=3.33 min.

Step B:8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3.7-dihydropurine-2,6-dione.HCl (2)

7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (100 mg,0.33 mmol) and 3-aminopyrrolidine (0.16 ml, 1.64 mmol) were dissolved in20 ml of 2-propanol and subjected to microwaves (method F, 150° C., 300W) for one hour. The solvent was evaporated and the crude product waspurified by preparative HPLC (method A1, R_(t)=6.45 min.). Evaporationof the solvent afforded the title compound as a brown oil.

Yield: 111 mg (87%).

¹H-NMR (MeOD, 400 MHz) δ: 2.04 (m, 1H), 2.37 (m, 1H), 3.30 (s, 3H), 3.51(s, 3H), 3.60-3.80 (m, 3H), 3.87-3.95 (m, 2H), 5.54 (d, 1H), 5.64 (d,1H), 7.14 (d, 2H), 7.23-7.35 (m, 3H) HPLC-MS (Method B): m/z=355 (M+1),R_(t)=1.49 min.

Example 3 (S)8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (3)

Step A: (S)(1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (3A)

7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (100 mg,0.33 mmol), (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (305 mg,1.64 mmol), and triethylamine (0.46 ml, 3.28 mmol) was dissolved in 20ml of 2-propanol and 5 ml of DMF and the mixture was subjected tomicrowaves (method F, 130° C., 300 W) for three hours. The solvent wasevaporated and the crude product was purified by preparative HPLC(method A1, R_(t)=11.75 min.). Evaporation of the solvent affordedcompound (3A) as a brown oil.

Yield: 130 mg (87%)

¹H-NMR (CDCl₃, 200 MHz) δ: 1.42 (s, 9H), 1.89 (m, 1H), 2.12 (m, 1H),3.34 (s, 3H), 3.37-3.79 (m, 7H), 4.22 (br. s, 1H), 4.97 (d, 1H), 5.49(d, 1H), 5.55 (d, 1H), 7.04 (m, 2H), 7.28 (m, 3H). HPLC-MS (Method B):m/z=455 (M+1), R_(t)=3.95 min.

Step B: (S)8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (3)

(S)(1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (3A) (130 mg, 0.29 mmol) was dissolved in 15 ml ofdiethyl ether, hydrochloric acid in diethyl ether (2.5 M, 5.72 ml, 14.3mmol) was added, and the mixture was stirred at room temperature for 24hours. The solvents were evaporated and the crude product was suspendedin dry DCM and collected by filtration to afford the title compound aswhite crystals.

Yield: 101 mg, (91%) Mp. 166-169° C.

¹H-NMR (MeOD, 300 MHz) δ: 2.05 (m, 1H), 2.37 (m, 1H), 3.29 (s, 3H), 3.52(s, 3H), 3.58-3.97 (m, 5H), 5.53 (d, 1H), 5.63 (d, 1H), 7.13 (d, 2H),7.21-7.36 (m, 3H).

HPLC-MS (Method B): m/z=355 (M+1), R_(t)=1.52 min.

Example 42-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.HCl (4)

2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(1A) (100 mg, 0.30 mmol) and 3-aminopyrrolidine (0.15 ml, 1.52 mmol)were reacted and purified as described in example 2, step B, to give thetitle compound as a yellow foam.

Yield: 108 mg (76%). Mp.186-189° C.

Prep. HPLC (method A1): R_(t)=6.19 min.

¹H-NMR (MeOD, 400 MHz) δ: 2.09 (m, 1H), 2.40 (m, 1H), 3.27 (s, 3H), 3.50(s, 3H), 3.59-3.78 (m, 3H), 3.88-3.99 (m, 2H), 5.70 (d, 1H), 5.79 (d,1H), 7.12 (d, 1H), 7.49 (dd, 1H), 7.62 (dd, 1H), 7.80 (d, 1H). HPLC-MS(Method B): m/z=380 (M+1), R_(t)=1.35 min.

Example 58-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (5)

NNC 0072-0000-5069-Step A:8-Chloro-7-(2-iodobenzyl)-1.3-dimethyl-3.7-dihydropurine-2,6-dione (5A)

8-Chlorotheophylline (8.5 g, 39.6 mmol) was dissolved in 400 ml of DMFand 2-iodobenzyl chloride (10.0 g, 39.6 mmol), potassium carbonate (5.47g, 39.6 mmol), and potassium iodide (10 mg, 0.06 mmol) were added. Themixture was stirred at room temperature for 7 days. Water (2500 ml) andEtOAc (800 ml) were added and the layers were separated. The aqueouslayer was extracted with 2×500 ml of EtOAc, and the combined organiclayer was washed with 500 ml of water, 500 ml of brine, dried oversodium sulphate, and filtered. The solvent was evaporated and the crudeproduct was crystallized from diethyl ether and petrol, to give compound(5A) as white crystals. The mother liquor was evaporated and resuspendedin diethyl ether and petrol, to give a second crop of compound (5A).

Combined yield: 10.4 g (61%). Mp. 177.6-178.2° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 3.37 (s, 3H), 3.61 (s, 3H), 5.59 (s, 2H),6.48 (d, 1H), 7.02 (t, 1H), 7.27 (t, 1H), 7.90 (d, 1H). HPLC-MS (MethodB): m/z=431 (M+1), R_(t)=3.94 min.

Step B:8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (5)

8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A)(100 mg, 0.23 mmol) and 3-aminopyrrolidine (0.13 ml, 1.16 mmol) werereacted and purified as described in example 2, step B, to give thecrude product, which was further suspended in dry DCM, and filtered toafford the title compound as white crystals.

Yield: 77 mg (64%).

Prep. HPLC (method A1): R_(t)=7.28 min.

¹H-NMR (MeOD, 200 MHz) δ: 2.02 (m, 1H), 2.35 (m, 1H), 3.27 (s, 3H),3.47-3.74 (m, 6H), 3.82-3.93 (m, 2H), 5.44 (d, 1H), 5.53 (d, 1H), 6.72(d, 1H), 7.04 (dd, 1H), 7.32 (dd, 1H), 7.92 (d, 1H). HPLC-MS (Method B):m/z=481 (M+1), R_(t)=1.76 min.

Preparative separation of compound (5) (Method E) gave compound (7) (Rt:20,0 min, 95,9% ee) and compound (15) (Rt: 16,5 min, 95.5% ee).

Example 68-(3-Aminoazepan-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (6)

Step A: N-(2-Oxoazepan-3-yl)-4-methylbenzenesulfonamide (6A)

DL-3-Amino-E-caprolactam (3 g, 23.4 mmol) was dissolved in 140 ml of dryDCM and dry triethylamine (4.5 ml) and 4-toluenesulfonyl chloride (4.5g, 23.6 mmol) were added.

The reaction was stirred for 3 days at room temperature and thenfiltered through celite. The filtrate was extracted with 50 ml of 1 Maqueous potassium hydrogen sulphate, 50 ml of saturated sodium hydrogencarbonate, 50 ml of water, and 50 ml of brine, and dried over sodiumsulphate. The solvent was evaporated and the residue suspended in drydichloromethane, and compound (6A) was collected by filtration. Themother liquor was evaporated and resuspended in DCM, to give a secondcrop of compound (6A) as white crystals.

Combined yield: 5.99 g (90%). Mp. 179.9-180.5° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 1.34 (m, 1H), 1.55-1.85 (m, 3H), 2.00 (m,1H), 2.17 (m, 1H), 2.40 (s, 3H), 3.10 (m, 2H), 3.81 (m, 1H), 5.86 (m,1H), 6.12 (d, 1H), 7.28 (d, 2H), 7.72 (d, 2H). HPLC-MS (Method B):m/z=283 (M+1), R_(t)=2.71 min.

Step B: N-(Azepan-3-yl)-4-methylbenzenesulfonamide (6B)

N-(2-Oxoazepan-3-yl)-4-methylbenzenesulfonamide (6A) (4.24 g, 15 mmol)was dissolved in 250 ml of dry THF under a nitrogen atmosphere, andlithium aluminium hydride (1.11 g, 30 mmol) was added slowly. Thereaction was heated to reflux for 20 hours and then quenched with wateruntil the effervescence ceased. Solid potassium carbonate was addeduntil a white suspension appeared, and the mixture was allowed to stirfor half an hour. The suspension was filtered through celite, which waswashed with 3×50 ml of EtOAc. The solvents were evaporated and theresidue was dissolved in 100 ml of EtOAc and 100 ml of water. The layerswere separated and the aqueous layer was extracted with 2×100 ml ofEtOAc. The combined organic layer was washed with brine, dried oversodium sulphate, and evaporated to give compound (6B) as an oil.

Yield: 2.89 g (71%).

¹H-NMR (CDCl₃, 300 MHz) δ: 1.37-1.74 (m, 6H), 2.41 (s, 3H), 2.55-2.93(m, 4H), 3.45 (m, 1H), 7.27 (d, 2H), 7.76 (d, 2H). HPLC-MS (Method B):m/z=269 (M+1), R_(t)=1.43 min.

Step C:N-(1-(7-Benzyl-1.3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)azepan-3-yl)-4-methylbenzenesulfonamide(6C)

7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (1.03 g,3.40 mmol) and N-(azepan-3-yl)-4-methylbenzenesulfonamide (6B) (1.00 g,3.73 mmol) were dissolved in 2-methoxyethanol (30 ml) and triethylamine(2.4 ml), and the mixture was heated to 120° C. for 2 days. The solventswere evaporated and the crude product was dissolved in 100 ml of EtOAcand 100 ml of water. The aqueous phase was acidified with 1M potassiumhydrogen sulphate until pH=2. The organic layer was separated andextracted with 50 ml of 1M aqueous potassium hydrogen sulphate, and 50ml of brine, and dried over sodium sulphate. The solvent was evaporatedand the crude product was purified by column chromatography on silicagel using EtOAc:heptane (1:1) as the eluent. Evaporation of the solventgave compound (6C) as a white foam.

Yield: 548 mg (30%). Mp. 80.2-88.2° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 1.22-1.84 (m, 6H), 2.41 (s, 3H), 3.00 (m,1H), 3.25 (dd, 1H), 3.47-3.72 (m, 6H), 5.37 (d, 1H), 5.59 (d, 1H), 7.03(d, 2H), 7.29 (m, 5H), 7.75 (d, 2H), 7.88 (d, 1H). HPLC-MS (Method B):m/z=537 (M+1), R_(t)=4.32 min.

Step D:8-(3-Aminoazepan-1-yl)-7-benzyl-1,3-dimethyl-3.7-dihydropurine-2,6-dione.TFA (6)

N-(1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)azepan-3-yl)-4-methylbenzenesulfonamide(6C) (100 mg, 0.19 mmol) was dissolved in hydrobromic acid (48%, 5 ml)and benzene (0.07 ml), and phenol (61.4 mg, 0.65 mmol) was added. Themixture was heated to reflux for three hours, and after cooling 20 ml ofEtOAc was added. The layers were separated, and the aqueous layer washedwith 20 ml of EtOAc. pH was adjusted to 11 with 10M sodium hydroxide.The aqueous layer was extracted with diethyl ether (3×20 ml), and thecombined organic layers were dried over sodium sulphate and the solventwas evaporated. The crude product was dissolved in 5 ml of DCM and 0.5ml of trifluoroacetic acid was added. The solvents were evaporated andthe crude product was purified by preparative HPLC (method A1,R_(t)=7.63 min). Evaporation of the solvent gave the title compound asan oil.

Yield: 8 mg (8%).

¹H-NMR (DMSO, 400 MHz) δ: 1.34 (m, 1H), 1.50 (m, 2H), 1.68 (m, 2H), 1.88(m, 1H), 3.20 (s, 3H), 3.30-3.50 (m, 5H), 3.81 (m, 1H), 5.46 (d, 1H),5.52 (d, 1H), 7.09 (m, 2H), 7.32 (m, 3H). HPLC-MS (Method B): m/z=383(M+1), R_(t)=2.00 min.

Example 7 (S)8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (7)

Step A: (S)(1-(7-(2-Iodobenzyl)-1,3-dimethyl-2,6-dioxo-1.2,3,6-tetrahydropurin-8-yl)Pyrrolidin-3-yl)carbamicacid tert-butyl ester (7A)

8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A)(100 mg, 0.23 mmol) and (3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine(216 mg, 1.16 mmol), and triethylamine (0.32 ml, 2.32 mmol) weredissolved in 20 ml of 2-propanol and the mixture was subjected tomicrowaves (method F, 130° C., 300 W) for three hours. The solvents wereevaporated and the crude product was purified by preparative HPLC(method A1, R_(t)=12.99 min.). Evaporation of the solvent affordedcompound (7A) as white crystals.

Yield: 132 mg (98%).

HPLC-MS (Method B): m/z=581 (M+1), R_(t)=4.42 min.

Step B: (S)8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (7)

(S)(1-(7-(2-Iodobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (7A) (132 mg, 0.23 mmol) was reacted and purifiedas described in example 3, step B, to give the title compound as whitecrystals.

Yield: 84 mg (72%). Mp. 119-223° C.

¹H-NMR (MeOD, 300 MHz) δ: 2.03 (m, 1H), 2.34 (m, 1H), 3.26 (s, 3H), 3.52(m, 4H), 3.65 (m, 2H), 3.90 (m, 2H), 5.45 (d, 1H), 5.52 (d, 1H), 6.73(d, 1H), 7.04 (m, 1H), 7.32 (m, 1H), 7.92 (d, 1H). HPLC-MS (Method B):m/z=481 (M+1), R_(t)=1.89 min.

Example 8 (S)2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.HCl (8)

Step A: (S)(1-(7-(2-Cyanobenzyl)-1,3-dimethyl-2.6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (8A)

2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(1 A) (100 mg, 0.30 mmol) was reacted with(3S)-(−)-3-(tert-butoxycarbonylamino)pyrrolidine (282 mg, 1.52 mmol),and purified as described in example 7, step A, to afford compound (8A)as white crystals.

Yield: 117 mg (81%).

Prep. HPLC, (method A1): R_(t)=11.50 min.

HPLC-MS (Method B): m/z=480 (M+1), R_(t)=3.75 min.

Step B: (S)2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.HCl (8)

(S)(1-(7-(2-Cyanobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (8A) (117 mg, 0.24 mmol) was reacted and purifiedas described in example 3, step B, to give the title compound as whitecrystals.

Yield: 51 mg (50%). Mp.104-117° C.

¹H-NMR (MeOD, 300 MHz) δ: 2.08 (m, 1H), 2.40 (m, 1H), 3.26 (s, 3H), 3.52(s, 3H), 3.53-3.78 (m, 3H), 3.92 (m, 2H), 5.71 (d, 1H), 5.78 (d, 1H),7.13 (d, 1H), 7.47 (m, 1H), 7.62 (m, 1H), 7.80 (d, 1H). HPLC-MS (MethodB): m/z=380 (M+1), R_(t)=1.34 min.

Example 98-(3-Aminopiperidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (9)

8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A)(100 mg, 0.23 mmol) and 3-aminopiperidine dihydrochloride (202 mg, 1.16mmol) were reacted and purified as described in example 1, step B, togive the title compound as oily brown crystals.

Yield: 19 mg (13%).

Prep. HPLC (method A1): R_(t)=7.70 min.

¹H-NMR (MeOD, 300 MHz) δ: 1.62 (m, 2H), 1.74 (m, 1H), 2.08 (m, 1H), 2.94(m, 1H), 3.18 (m, 2H), 3.28 (s, 3H), 3.46 (m, 1H), 3.54 (s, 3H), 3.70(m, 1H), 5.35 (s, 2H), 6.78 (d, 1H), 7.04 (m, 1H), 7.32 (m, 1H), 7.92(d, 1H).

HPLC-MS (Method B): m/z=495 (M+1), R_(t)=2.09 min.

Example 108-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (10)

Step A:7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(10A)

8-Chlorotheophylline (10 g, 46.6 mmol) was dissolved in 250 ml of DMFand 8 ml of DIEA, and 2-bromobenzyl bromide (12.2 g, 48.9 mmol) wasadded. The mixture was stirred at 65° C. for 2 hours. The reactionmixture was added 20 ml of EtOAc and 250 ml of cold water. The whiteprecipitate was collected by filtration to afford compound (10A) aswhite crystals.

Yield: 17.2 g (96%). Mp. 165.4-166.7° C.

¹H-NMR (CDCl₃, 300 MHz) δ: 3.37 (s, 3H), 3.60 (s, 3H), 5.67 (s, 2H),6.57 (d, 1H), 7.20 (m, 2H), 7.62 (d, 1H). HPLC-MS (Method B): m/z=385(M+2), R_(t)=3.77 min.

Step B:8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (10)

7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(10A) (100 mg, 0.26 mmol) and 3-aminopiperidine dihydrochloride (226 mg,1.31 mmol) were dissolved in 2-propanol (20 ml), triethylamine (0.109ml, 0.78 mmol) and DMF (5 ml) and subjected to microwaves (method F,130° C., 300 W) for ten hours. The solvents were evaporated and thecrude product was purified by preparative HPLC, (method A1, R_(t)=7.52min.) to give the title compound as a brown oil.

Yield: 10 mg (7%).

HPLC-MS (Method B): m/z=447 (M+), R_(t)=2.05 min.

Example 11 (R)8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA(1)

Step A: (R)(1-(7-(2-Bromobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (11A)

7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(10A) (100 mg, 0.26 mmol) and(3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (243 mg, 1.30 mmol)were reacted and purified as described in example 3, step A, to givecompound (11A) as brown crystals.

Yield: 44 mg (32%). Mp. 104-106° C.

Prep. HPLC, (method A1): Rt=12.66 min.

¹H-NMR (MeOD, 200 MHz) δ: 1.40 (s, 9H), 1.83 (m, 1H), 2.07 (m, 1H), 3.25(s, 3H), 3.37 (m, 1H), 3.48-3.78 (m, 6H), 4.04 (m, 1H), 5.57 (s, 2H),6.74 (d, 1H), 7.23 (m, 2H), 7.62 (m, 1H).

HPLC-MS (Method B): m/z=535 (M+2), R_(t)=4.08 min

Step B: (R)8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1.3-dimethyl-3.7-dihydropurine-2,6-dione.TFA (11)

(R)(1-(7-(2-Bromobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl)pyrrolidin-3-yl)carbamicacid tert-butyl ester (11A) (44 mg, 0.08 mmol) was dissolved in MeCN (1ml), water (1 ml), and TFA (0.32 ml), and the mixture was stirred atroom temperature for 2 days.

The solvents were evaporated and the crude product was purified bypreparative HPLC (method A1, R_(t)=6.92 min.) to give the title compoundas a brown oil.

Yield: 40 mg (88%).

¹H-NMR (MeOD, 300 MHz) δ: 2.05 (m, 1H), 2.35 (m, 1H), 3.25 (s, 3H),3.50-3.74 (m, 6H), 3.90 (m, 2H), 5.54 (d, 1H), 5.61 (d, 1H), 6.80 (dd,1H), 7.21 (dt, 1H), 7.30 (dt, 1H), 7.63 (dd, 1H). HPLC-MS (Method B):m/z=433 (M+), R_(t)=1.83 min.

Example 12 (S)8-(3-Aminopyrrolidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (12)

7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(10A) (100 mg, 0.26 mmol) and (S)-(−)-3-aminopyrrolidine (112 mg, 1.30mmol) were dissolved in 2-propanol (20 ml) and DMF (5 ml) and subjectedto microwaves (method F, 130° C., 300W) for 10 hours. The solvents wereevaporated and the crude product was purified by preparative HPLC(method A1, R_(t)=6.92 min.) to give the title compound as browncrystals.

Yield: 50 mg (41%). Mp. 215-217° C.

¹H-NMR (MeOD, 200 MHz) δ: 2.04 (m, 1H), 2.33 (m, 1H), 3.25 (s, 3H),3.48-3.78 (m, 6H), 3.90 (m, 2H), 5.53 (d, 1H), 5.60 (d, 1H), 6.80 (dd,1H), 7.25 (m, 2H), 7.63 (dd, 1H).

HPLC-MS (Method B): m/z=433 (M+), R_(t)=1.80 min.

Example 13 (R)8-(3-Aminopyrrolidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (13)

7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (100 mg,0.33 mmol) and (R)-(+)-3-aminopyrrolidine (141 mg, 1.64 mmol) werereacted and purified as described in example 12 to give the titlecompound as brown crystals.

Yield: 73 mg (57%). Mp. 103-114° C.

Prep. HPLC, (method A1): Rt=6.38 min.

¹H-NMR (MeOD, 200 MHz) δ: 2.08 (m, 1H), 2.35 (m, 1H), 3.27 (s, 3H), 3.49(s, 3H), 3.55-4.00 (m, 5H), 5.52 (d, 1H), 5.63 (d, 1H), 7.12 (m, 2H),7.29 (m, 3H). HPLC-MS (Method B): m/z=355 (M+1), R_(t)=1.55 min.

Example 14 (R)2-(8-(3-Aminopyrrolidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.HCl (14)

2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(1 A) (100 mg, 0.30 mmol) and (R)-(+)-3-aminopyrrolidine (131 mg, 1.57mmol) were reacted and purified as described in example 2, step B. togive the title compound as brown crystals.

Yield: 125 mg (99%). Mp. 202-204° C.

Prep. HPLC, (method A1): Rt=6.17 min.

¹H-NMR (MeOD, 200 MHz) δ: 2.12 (m, 1H), 2.41 (m, 1H), 3.22 (s, 3H), 3.49(s, 3H), 3.55-4.04 (m, 5H), 5.70 (d, 1H), 5.78 (d, 1H), 7.11 (d, 1H),7.47 (t, 1H), 7.61 (t, 1H), 7.78 (d, 1H).

HPLC-MS (Method B): m/z=380 (M+1), R_(t)=1.38 min.

Example 15 (R)8-(3-Aminopyrrolidin-1-yl)-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (15)

8-Chloro-7-(2-iodobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione (5A)(100 mg, 0.23 mmol) and (R)-(+)-3-aminopyrrolidine (100 mg, 1.16 mmol)were reacted and purified as described in example 2, step B. to give thetitle compound as white crystals.

Yield: 61 mg (51%). Mp. 233-235° C.

Prep. HPLC, (method A1): R_(t)=7.24 min.

¹H-NMR (MeOD, 200 MHz) δ: 2.05 (m, 1H), 2.34 (m, 1H), 3.25 (s, 3H),3.46-3.76 (m, 6H), 3.90 (m, 2H), 5.43 (d, 1H), 5.52 (d, 1H), 6.72 (dd,1H), 7.03 (dt, 1H), 7.32 (dt, 1H), 7.91 (dd, 1H). HPLC-MS (Method B):m/z=481 (M+1), R_(t)=1.88 min.

Example 16 General Procedure (E) (R)2-[8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]-benzonitrile.HCl (16)

Step A:2-(8-Chloro-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(16A)

From 2-Cyanobenzyl bromide.

Yield: 28.6 g (93%). Mp. 222.5-223.7° C.

¹H-NMR (DMSO, 300 MHz) δ: 7.93 (d, 1H), 7.66 (t, 1H), 7.52 (t, 1H), 7.07(d, 1H), 5.75 (s, 2H), 3.42 (s, 3H), 3.20 (s, 3H). HPLC-MS (Method B):m/z=330 (M), R_(t)=2.93 min.

Step B: (R)1-[7-(2-Cyanobenzyl)-1,3-dimethyl-2,6-dioxo-1,2.3.6-tetrahydropurin-8-yl]-piperidin-3-yl)carbamicacid tert-butyl ester (16B)

From (16A) (4 g, 12.1 mmol)

Yield: 4.8 g (80%)

Step C: (R)2-[8-(3-Aminopiperidin-1-yl)-1.3-dimethyl-2,6-dioxo-1.2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.HCL (16)

From (16B) (4.8 g, 9.7 mmol)

Yield: 2.49 g (59%) of the title compound.

¹H-NMR (CDCl3, 200 MHz) δ: 8.59(s, 2H), 7.67(m, 1H), 7.56(m, 1H),7.39(m, 1H), 7.17(m, 1H), 5.64(s, 2H), 3.95(s, 1H), 3.68(m, 2H), 3.51(s,4H), 3.30(s, 3H), 3.01(s, 2H), 2.00(m, 2H), 1.65(s, 1H). ¹³C-NMR (CDCl3,200 MHz) δ:155.76, 154.48, 151.46, 147.16, 140.17, 133.56, 133.18,128.37, 127.47, 117.18, 110.54, 104.98, 58.07, 52.26, 51.54, 47.13,46.91, 30.00, 27.91, 27.47, 21.72, 18.35.

Example 17 General Procedure (E) (R)8-(3-Aminopiperidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (17)

Step A: 7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2.6-dione (17A)

From 8-Chlorotheophylline (50 g, 233 mmol) and benzyl bromide.

The reaction mixture was evaporated to dryness in vacuo, dissolved inDCM (400 ml) and water (250 ml). The separated aqueous phase wasextracted with DCM (150 ml), and the combined DCM phases were washedwith brine, dried (MgSO₄), and evaporated in vacuo.

Yield: 73.6 g (app. 100%). Mp. 152-154° C.

¹H-NMR (CDCl3, 200 MHz) δ: 7.35 (m, 5H), 5.55 (s, 2H), 3.55 (s, 3H),3.42 (s, 3H).

HPLC-MS (Method B): m/z=305 (M+1), R_(t)=3.33 min.

Step B: (R)[1-(7-Benzyl-1,3-dimethyl-2,6-dioxo-1.2,3,6-tetrahydropurin-8-yl)piperidin-3-yl]carbamicacid tert-butyl ester (17B)

From (17A) (4 g, 13.1 mmol)

Yield: 5.1 g (84%)

Step C: (R)8-(3-Aminopiperidin-1-yl)-7-benzyl-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (17)

From (17B) (4.1 g, 10.9 mmol)

Yield: 2.6 g (67%) of the title compound.

¹H-NMR (CDCl3, 200 MHz) δ: 7.29(m, 5H), 5.45(dd, 2H), 3.72(m, 2H),3.52(s, 4H), 3.37(s, 3H), 3.28(m, 1H), 3.10(m, 1H), 2.93(m, 1H), 2.14(m,1H), 1.84(m, 2H), 1.57(s, 1H). HPLC-MS (Method B): m/z=369 (M+1),R_(t)=3.69 min.

Example 18 General Procedure (E) (R)8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.HCl (18)

Step A:8-Chloro-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione(18A)

From 8-Chorotheophylline (10 g, 47 mmol) and 2-methylbenzyl bromide(13.6 ml, 103 mmol).

The benzyl bromide was added in two portions. First half at reactionstart as described in general procedure (E), and the other half after 24hours as the reaction had not completed.

Yield: 12.8 g (86%). Mp.164.9-165.2° C.

¹H-NMR (CDCl3, 200 MHz) δ: 7.3-7.05 (m, 3H), 6.55 (d, 1H), 5.55 (s, 2H),3.57 (s, 3H), 3.34 (s, 3H), 2.42 (s, 3H). HPLC-MS (Method B): m/z=319(M+1), R_(t)=3.76 min.

Step B: (R)(1-[1,3-Dimethyl-7-(2-methylbenzyl)-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl]piperidin-3-yl)carbamicacid tert-butyl ester (18B)

From (18A) (4 g, 12.5 mmol)

Yield: 4.9 g (82%).

Step C: (R)8-(3-Aminopiperidin-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.HCl (18)

From (18B) (4.9 g, 10.2 mmol)

Yield: 3.27 g (76%) of the title compound.

¹H-NMR (CDCl3, 200 MHz) δ: 7.14(m, 3H), 6.67(d, 1H), 5.39(d, 2H),3.80(s, 3H), 3.71(m, 1H), 3.52(s, 4H), 3.34(m, 4H), 3.02(s, 2H), 2.38(s,3H), 2.10(s, 1H), 1.81(s, 2H), 1.54(s, 1H)

¹³C-NMR (CDCl3, 200 MHz) δ:155.74, 154.53, 151.83, 147.29, 134.83,134.54, 130.55, 127.61, 126.48, 124.62, 105.44, 52.03, 51.01, 46.88,29.85, 27.92, 27.65, 22.11, 19.08.

Example 19 General Procedure (E) (R)8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (19)°

Step A:8-Chloro-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione(19A)

From 8-Chorotheophylline (10 g, 47 mmol)) and 2-chlorobenzyl chloride(19.4 ml, 153.9 mmol). The 2-chlorobenzyl chloride was added in threeportions. First third at reaction start as described in generalprocedure (E), and the other thirds after 24 and 48 hours respectivelyas the reaction had not completed. Total reaction time 7 days at RT. Dueto incomplete precipitation in water the product was extracted with DCM(700 and 300 ml), dried (MgSO₄), and evaporated to dryness in vacuo.Excess 2-chlorobenzyl bromide was removed by washing the product inEt₂O.

Yield: 15.6 g (99%). Mp.189.7-191.8° C.

¹H-NMR (CDCl3, 200 MHz) δ: 7.42 (d, 1H), 7.30-7.12 (m, 2H, 6.67 (d, 1H),5.7 (s, 2H), 3.57 (s, 3H), 3.35 (s, 3H). HPLC-MS (Method B): m/z=339(M+1), R_(t)=3.90 min.

Step B: (R)(1-[7-(2-Chlorobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl]piperidin-3-yl)carbamicacid tert-butyl ester (19B)

From (19A) (5.89 g, 17.4 mmol)

Yield: 8.87 g (app. 100%).

Step C: (R)8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (19)

From (19B) (8.87 g, 17.6 mmol)

Yield: 2.49 g (59%) of the title compound.

¹H-NMR (CDCl3, 200 MHz) δ: 8.57(s, 3H), 7.27(m, 3H), 6.87(m, 1H),5.47(m, 2H), 3.19-3.82(m, 9H), 2.97(s, 2H), 2.12(s, 1H), 1.84(m, 2H),1.53(s, 1H)

¹³C-NMR (CDCl3, 200 MHz) δ: 155.53, 154.34, 151.56, 147.16, 132.02,129.64, 129.02, 127.39, 127.02, 105.27, 74.83, 51.93, 51.07, 46.98,46.72, 29.93, 27.73, 22.05.

Example 20 General Procedure (E) (R)8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (20)

Step A: 7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (20A)

From 8-Chorotheophylline (10 g, 46.6 mol) and 2-bromobenzyl bromide(12.2 g, 48.93 mol).

Yield: 17.2 g (96%).

¹H-NMR (CDCl3, 200 MHz) δ: 7.62(m, 1H), 7.21(m, 2H), 6.58(m, 1H),5.67(s, 2H), 3.60(s, 3H), 3.38(s, 3H). HPLC-MS (Method B): m/z=384(M+1).

Step B: (R)(1-[7-(2-Bromobenzyl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-8-yl]piperidin-3-yl)carbamicacid tert-butyl ester (20B) From (20A) (6.08 g, 15.8 mmol)

Yield: 8.78 g (app. 100%).

Step C: (R)8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.HCl (20)

From (20B) (8.78 g, 16.1 mmol)

Yield: 3.73 g (52%) of the title compound.

¹H-NMR (MeOD, 200 MHz) δ:

¹³C-NMR (CDCl₃, 200 MHz) 6:155.52, 154.28, 151.55, 147.16, 135.57,132.92, 129.28, 128.01, 127.03, 121.78, 105.23, 51.95, 51.01, 49.19,47.01, 29.95, 27.93, 27.81, 22.22.

Example 21 General Procedure (G) (R)8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydro-purine-2,6-dione.TFA (21)

Yield: 130 mg (41%)

Prep. HPLC, (method A1): R_(t)=8.86 min.

HPLC-MS (Method B): m/z=551.1 (M+), R_(t)=2.83 min.

Example 22 General Procedure (G) (R)8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA (22)

Yield: 257 mg (82%)

Prep. HPLC, (method A1): Rt=9.20 min.

HPLC-MS (Method B): m/z=539.2 (M+1), R_(t)=3.23 min.

Example 23 General Procedure (G) (R)8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-1-phenethyl-3,7-dihydropurine-2,6-dione.TFA (23)

Yield: 34 mg (13%)

Prep. HPLC, (method A1): R_(t)=9.83 min.

HPLC-MS (Method B): m/z=493.2 (M+), R_(t)=2.94 min.

Example 24 General Procedure (G) (R)2-[8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile(24)

¹H NMR (CDCl₃): δ=8.25 (s, br, 2H), 7.6 (d, 1H), 7.3 (m, 6H), 6.85 (dd,1H), 6.3 (s, br, 1H), 5.45 (s, 1H), 5.35 (s, 2H), 5.25 (s, 1H), 3.65 (m,3H), 3.45 (s, 3H), 3.0 (m, 2H), 2.15-1.3 (m, 4H). HPLC-MS (Method B):m/z=505 (M+1), R_(t)=2.9 min.

Example 25 General Procedure (D)

2-[8-(3-Aminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile(25)

¹H NMR (DMSO-d₆): δ7.87 (d, 1H), 7.80 (d, 1H), 7.65 (t, 1H), 7.57 (t,1H), 7.49 (t, 1H), 7.42 (t, 1H), 7.12 (d, 2H), 5.54 (s, 2H), 5.15 (s,2H), 3.42 (s, 3H), 2.86 (m, 1H), 2.64 (m, 2H), 1.78 (m, 1H), 1.66 (m,1H), 1.47 (m, 1H), 1.15 (m, 1H). HPLC-MS (Method B): m/z=495 (M+1) 518(M+23), R_(t)=2.28 min.

Example 26 General Procedure (D) (R)2-[8-(3-Aminopiperidin-1-yl)-7-(2-cyanobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile.TFA (26)

¹H NMR (DMSO-d₆): δ8.1 (s, 3H), 7.87 (d, 1H), 7.80 (d, 1H), 7.70-7.33(m, 4H), 7.095 (dd, 2H), 5.54 (s, 2H), 5.13 (s, 2H), 3.65-3.53 (m, 1H),3.43 (s, 3H), 3.40-3.26 (m, 1H), 3.26-3.05 (m, 2H), 3.01-2.87 (m, 1H),2.04-1.68 (m, 2H), 1.65-1.44 (m, 2H). HPLC-MS (Method B): m/z=495 (M+1),R_(t)=2.503 min.

Example 27 General Procedure (E) (R)2-[8-(3-(R)-Aminopiperidin-1-yl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.HCl (27)

¹H NMR (DMSO-d₆): δ 10.95 (s, 1H), 8.24 (s, 3H), 7.875 (d, 1H), 7.65 (t,1H), 7.49 (t, 1H), 7.085 (d, 1H), 5.50 (s, 2H), 3.62-3.49 (m, 2H),3.19-3.02 (m, 2H), 2.87 (t, 1H), 2.02-1.42 (m, 4H). HPLC-MS (Method B):m/z=380 (M+1), R_(t)=1.361 min.

Example 28 General Procedure (E) (R)8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.HCl (28)

¹H NMR (DMSO-d₆): δ 10.95 (s, 1H), 8.35 (s br, 3H), 7.50 (d, 2H), 7.31(dt, 2H), 6.87 (d, 1H), 5.38 (s, 2H), 3.56 (m, 1H), 3.36 (s, 3H), 3.20(s br, 1H), 3.18-3.00 (m, 2H), 2.79 (t, 1H), 1.91 (s br, 1H), 1.72 (sbr, 1H), 1.60-1.30 (m, 2H).

Example 29 General Procedure (G) (R)8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydropurine-2,6-dione.HCl (29)

¹H NMR (DMSO-d₆): δ8.70 (s, 1H), 8.34 (s, 3H), 7.65-7.70(m, 2H), 7.54(d, 1H), 7.34 (t, 1H), 7.24 (t, 1H), 6.84 (d, 1H), 5.34 (s, 2H), 5.18(s, 2H), 3.60-3.66 (m, 1H), 3.46 (s, 3H), 3.05-3.35(m, 3H), 2.80-2.90(m,1H), 1.40-2.00(m, 4H). HPLC-MS (Method B): m/z=558 (M+1), R_(t)=3.90min.

Example 30 General Procedure (G) (R)2-[8-(3-Aminopiperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-thiophen-3-yl-ethyl)-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA (30)

¹H NMR (DMSO-d₆): δ 8.68-8.70 (m, 1H), 8.10-8.20 (m, 3H), 7.86-7.90 (d,1H), 7.45-7.70 (m, 4H), 7.05-7.10 (d, 1H), 5.53(s, 2H), 5.18 (s, 2H),3.56-3.64 (m, 1H), 3.46 (s, 3H), 3.10-3.25(m, 2H), 2.90-3.00(m, 1H),1.50-2.20(m, 4H). HPLC-MS (Method B): m/z=504, R_(t)=2.23 min.

Example 31 General Procedure (F)8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(3-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione(31)

HPLC-MS (Method A3): m/z=449 (M+1), R_(t)=3.60 min.

Example 32 General Procedure (F)

8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-chloro-benzyl)-3,7-dihydro-purine-2,6-dione(32)

HPLC-MS (Method A3): m/z=465 (M+1), R_(t)=3.40 min.

Example 33 General Procedure (F)

8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-bromo-benzyl)-3,7-dihydro-purine-2,6-dione(33)

HPLC-MS (Method A3): m/z=508 (M+1), R_(t)=3.50 min.

Example 34 General Procedure (F)

8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione(34)

HPLC-MS (Method A3): m/z=445 (M+1), R_(t)=3.50 min.

Example 35 General Procedure (F)

8-(3-Amino-piperidin-1-yl)-3,7-dibenzyl-3,7-dihydro-purine-2,6-dione(35)

HPLC-MS (Method A3): m/z=431 (M+1), R_(t)=3.40 min.

Example 36 General Procedure (F)

8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(3,5-difluoro-benzyl)-3,7-dihydro-purine-2,6-dione(36)

HPLC-MS (Method A3): m/z=467 (M+1), R_(t)=3.50 min.

Example 37 General Procedure (F)8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2,5-difluoro-benzyl)-3,7-dihydro-purine-2,6-dione(37)

HPLC-MS (Method A3): m/z=467 (M+1), R_(t)=3.30 min.

Example 38 General Procedure (F)8-(3-Amino-piperidin-1-yl)-3-benzyl-7-(2-difluoromethoxy-benzyl)-3,7-dihydro-purine-2,6-dione(38)

HPLC-MS (Method A3): m/z=497 (M+1), R_(t)=3.50 min.

Example 39 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(3-fluoro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione(39)

HPLC-MS (Method A3): m/z=373 (M+1), R_(t)=2.30 min.

Example 40 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione(40)

HPLC-MS (Method A3): m/z=389 (M+1), R_(t)=2.40 min.

Example 41 General Procedure (F)8-(3-Amino-piperidin-1-yl)-3-methyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione(41)

HPLC-MS (Method A3): m/z=369 (M+1), R_(t)=2.40 min.

Example 42 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-3,7-dihydro-purine-2,6-dione(42)

HPLC-MS (Method A3): m/z=355 (M+1), R_(t)=2.10 min.

Example 43 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(3,5-difluoro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione(43)

HPLC-MS (Method A3): m/z=391 (M+1), R_(t)=2.85 min.

Example 44 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(3-fluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione(44)

HPLC-MS (Method A3): m/z=387 (M+1), R_(t)=3.10 min.

Example 45 General Procedure (F)8-(3-Amino-piperidin-1-yl)-1,3-dimethyl-7-(2-methyl-benzyl)-3,7-dihydro-purine-2,6-dione(45)

¹H NMR (CDCl₃): δ=8.1(br. s, 3H), 7.1(m, 3H), 6.6(d, 1H), 5.4(q, 2H),3.4-3.6(m, 6H), 3.3(s, 3H), 3.05(br. s, 2H), 1.4-2.0(m, 4H). ¹³C-NMR(CDCl₃) δ=155.60, 154.79, 152.01, 135,10, 134.61, 130.96, 128.06,126.86, 124.93, 105.83, 75.09, 52.02, 51.24, 50.73, 47.10, 46.72, 30.05,28.29, 21.12, 19.26. HPLC-MS (Method A3): m/z=383 (M+1), R_(t)=3.20 min.

Example 46 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(3,5-difluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione(46)

HPLC-MS (Method A3): m/z=405 (M+1), R_(t)=3.10 min.

Example 47 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(2,5-difluoro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione(47)

HPLC-MS (Method A3): m/z=405 (M+1), R_(t)=2.80 min.

Example 48 General Procedure (F)8-(3-Amino-piperidin-1-yl)-7-(2-difluoromethoxy-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione(48)

HPLC-MS (Method A3): m/z=435 (M+1), R_(t)=3.10 min.

Example 49 General Procedure (A)8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione(49)

¹H NMR (DMSO-d₆): δ8.03 (d, 2H), 7.95 (s br, 3H), 7.70 (t, 1H), 7.56 (t,2H), 7.49 (m, 1H), 7.31 (m, 2H), 6.88 (d, 1H), 5.39 (s, 2H), 5.30 (s,2H), 3.63 (d, 1H), 3.25-3.15 (m, 2H), 2.05-1.20 (m, 5H). HPLC-MS (MethodC): m/z=507 (M+1), R_(t)=4.68 min.

Example 50 General Procedure (G)8-(R-3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione(50)

¹H NMR (DMSO-d₆): δ8.70 (s, 3H), 8.035 (d, 2H), 7.70 (t, 1H), 7.57 (t,2H), 7.53-7.45 (m, 1H), 7.38-7.25 (m, 2H), 6.93-6.82 (m, 1H), 5.405 (d,2H), 5.30 (s, 2H), 6.64 (d, 1H), 3.47 (s, 3H), 3.21-3.06 (m, 3H),2.94-2.80 (m, 1H), 2.02-1.34 (m, 4H). HPLC-MS (Method B): m/z=507 (M+1),R_(t)=2,868 min.

Example 51 General Procedure (A)2-[8-(3-Aminopiperidin-1-yl)-7-(2-bromobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl]benzonitrile(51)

¹H NMR (DMSO-d₆): δ7.99 (s br, 3H), 7.80 (d, 1H), 7.67 (d, 1H), 7.58 (t,1H), 7.42 (t, 1H), 7.34 (t, 1H), 7.25 (t, 1H), 7.16 (d, 1H), 6.87 (d,1H), 5.34 (s, 2H), 5.15 (s, 2H), 3.62 (m, 1H), 3.40 (m, 2H), 3.45 (s,3H), 3.20-3.05 (m, 2H), 1.95 (m, 1H), 1.80 (m, 1H), 1.55 (m, 2H).

HPLC-MS (Method C): m/z=548 (M+1), R_(t)=4.68

Example 52 General Procedure (A)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione(52)

¹H NMR (DMSO-d₆): δ8.03 (d, 2H), 7.96 (s br, 3H), 7.72-7.65 (m, 2H),7.56 (t, 2H), 7.35 (t, 1H), 7.25 (t, 1H), 6.83 (d, 1H), 5.34 (s, 2H),5.30 (s, 2H), 3.62 (m, 1H), 3.47 (s, 3H), 3.20-3.05 (m, 2H), 1.95 (m,1H), 1.80 (m, 1H), 1.55 (m, 2H). HPLC-MS (Method C): m/z=551 (M+1),R_(t)=4.80

Example 53 General Procedure (D)8-(3-Amino-piperidin-1-yl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-7-(2-trifluoromethyl-benzyl)-3,7-dihydro-purine-2,6-dione(53)

HPLC-MS (Method A3): m/z=541 (M+1), R_(t)=4.30 min.

Example 54 General Procedure (D)8-(3-Amino-piperidin-1-yl)-1-(2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-7-(2-chloro-benzyl)-3-methyl-3,7-dihydro-purine-2,6-dione(54)

HPLC-MS (Method A3): m/z=564 (M+1), R_(t)=4.60 min.

Example 55 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(55)

HPLC-MS (Method A3): m/z=525 (M+1), R_(t)=4.10 min.

Example 56 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-(2-cyclopropyl-2-oxo-ethyl)-3-methyl-3,7-dihydro-purine-2,6-dione(56)

HPLC-MS (Method A3): m/z=516 (M+1), R_(t)=3.40 min.

Example 57 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2,6-dimethoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(57)

HPLC-MS (Method A3): m/z=612 (M+1), R_(t)=4.20 min.

Example 58 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-thiophen-3-yl-ethyl)-3,7-dihydro-purine-2,6-dione(58)

HPLC-MS (Method A3): m/z=558 (M+1), R_(t)=3.90 min.

Example 59 General procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(4-chloro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(59)

HPLC-MS (Method A3): m/z=586 (M+1), R_(t)=4.50 min.

Example 60 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-2-p-tolyl-ethyl)-3,7-dihydro-purine-2,6-dione(60)

HPLC-MS (Method A3): m/z=566 (M+1), R_(t)=4.40 min.

Example 61 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2-chloro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(61)

HPLC-MS (Method A3): m/z=586 (M+1), R_(t)=4.30 min.

Example 62 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(62)

HPLC-MS (Method A3): m/z=582(M+1), R_(t)=4.30 min.

Example 63 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(2-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(63)

HPLC-MS (Method A3): m/z=582 (M+1), R_(t)=4.20 min.

Example 64 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-butyl)-3,7-dihydro-purine-2,6-dione(64)

HPLC-MS (Method A3): m/z=504 (M+1), R_(t)=0.90 min.

Example 65 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-3-methyl-1-(2-oxo-1-phenyl-pyrrolidin-3-yl)-3,7-dihydro-purine-2,6-dione(65)

HPLC-MS (Method A3): m/z=593 (M+1), R_(t)=4.00 min.

Example 66 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-bromo-benzyl)-1-[2-(3-chloro-phenyl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione(66)

HPLC-MS (Method A3): m/z=586 (M+1), R_(t)=4.60 min.

Example 67 General Procedure (D)2-{8-(3-Amino-piperidin-1-yl)-1-[2-(2,6-difluoro-phenyl)-2-oxo-ethyl]-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl}-benzonitrile(67)

HPLC-MS (Method A3): m/z=534(M+1), R_(t)=3.90 min.

Example 68 General Procedure (D)2-[8-(3-Amino-piperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-thiophen-3-yl-ethyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile(68)

HPLC-MS (Method A3): m/z=504 (M+1), R_(t)=0.90 min.

Example 69 General Procedure (D)2-[8-(3-Amino-piperidin-1-yl)-1-(2-benzo[b]thiophen-3-yl-2-oxo-ethyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile(69)

HPLC-MS (Method A3): m/z=554 (M+1), R_(t)=4.30 min.

Example 70 General Procedure (D)2-[8-(3-Amino-piperidin-1-yl)-3-methyl-2,6-dioxo-1-(2-oxo-2-phenyl-ethyl)-1,2,3,6-tetrahydro-purin-7-ylmethyl]-benzonitrile(70)

HPLC-MS (Method A3): m/z=498 (M+1), R_(t)=3.60 min.

Example 71 General Procedure (D)2-{8-(3-Amino-piperidin-1-yl)-1-[2-(3-fluoro-phenyl)-2-oxo-ethyl]-3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-purin-7-ylmethyl}-benzonitrile(71)

HPLC-MS (Method A3): m/z=516 (M+1), R_(t)=3.80 min.

Example 72 General Procedure (D)8-(3-Amino-piperidin-1-yl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-7-(3-trifluoromethoxy-benzyl)-3,7-dihydro-purine-2,6-dione(72)

HPLC-MS (Method A3): m/z=557 (M+1), R_(t)=4.50 min.

Example 73 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-fluoro-6-trifluoromethyl-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione(73)

HPLC-MS (Method A3): m/z=559 (M+1), R_(t)=4.10 min.

Example 74 General Procedure (D)8-(3-Amino-piperidin-1-yl)-7-(2-fluoro-5-trifluoromethyl-benzyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione(74)

HPLC-MS (Method A3): m/z=559 (M+1), R_(t)=4.30 min.

Example 752-(8-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile.TFA (75)

Step A: 8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.(75A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-chlorobenzyl bromidewere reacted and purified as described in the General procedure G, stepA, to afford compound (75A).

HPLC-MS (Method B): m/z=371 (M+1), R_(t) 3.031 min.

Step B:2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile(75B)

8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (75A)and alpha-bromo-o-tolunitrile were reacted and purified as described inthe General procedure G, Step B, to afford 75B as white crystals.

Yield: 1.66 g (85%).

HPLC-MS (Method B): m/z=486 (M+1), R_(t)=4.733 min.

Step C:2-(8-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile.TFA (75)

2-(8-Bromo-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-1-ylmethyl)benzonitrile(75B) (250 mg, 0.5 mmol) and azepan-3-ylamine (294 mg, 2.5 mmol), andtriethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO andthe mixture was subjected to microwaves (method F, 100° C., 300 W) forfive hours. To the reaction mixture was added 100 ml of water and 100 mlof dichloromethane, and the organic layer was separated and dried oversodium sulfate. The solvents were evaporated and the crude product waspurified by preparative HPLC (method A1, R_(t)=8.77 min.). Evaporationof the solvent afforded the title compound as an yellow oil.

Yield: 166 mg (51%).

HPLC-MS (Method B): m/z=518 (M+), R_(t)=3.09 min.

Example 768-(3-Aminoazepan-1-yl)-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.TFA (76)

8-Bromo-7-(2-chlorobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (75A)(185 mg, 0.5 mmol) and azepan-3-ylamine (513 mg, 4.5 mmol), andtriethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO andthe mixture was subjected to microwaves (method F, 100° C., 300 W) forfour hours. To the reaction mixture was added 100 ml of water and 100 mlof dichloromethane, and the organic layer was separated and dried overmagnesium sulfate. The solvents were evaporated and the crude productwas purified by preparative HPLC (method A1, R_(t)=7.12 min.).Evaporation of the solvent afforded the title compound as an yellow oil.

Yield: 110 mg (43%).

HPLC-MS (Method B): m/z=403 (M+1), R_(t)=1.87 min.

Example 778-(3-Aminoazepan-1-yl)-7-benzyl-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione.TFA (77)

Step A: 7-Benzyl-8-bromo-3-methyl-3,7-dihydropurine-2,6-dione (77A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and benzyl bromide werereacted and purified as described in the General procedure G, step A, toafford 77A.

HPLC-MS (Method B): m/z=335 (M+)

Step B:7-Benzyl-8-bromo-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione(77B)

7-Benzyl-8-bromo-3-methyl-3,7-dihydropurine-2,6-dione (77A) and2-bromoacetophenone were reacted and purified as described in theGeneral procedure G, Step B, to afford 77B.

HPLC-MS (Method B): m/z=453 (M+).

Step C:8-(3-Aminoazepan-1-yl)-7-benzyl-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione.TFA (77)

7-Benzyl-8-bromo-3-methyl-1-(2-oxo-2-phenylethyl)-3,7-dihydropurine-2,6-dione(77B) (227 mg, 0.5 mmol) and azepan-3-ylamine (342 mg, 3 mmol), andtriethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO andthe mixture was subjected to microwaves (method F, 100° C., 300 W) forfive hours. To the reaction mixture was added 100 ml of water and 100 mlof dichloromethane, and the organic layer was separated and dried oversodium sulfate. The solvents were evaporated and the crude product waspurified by preparative HPLC (method A1, R_(t)=8.77 min.). Evaporationof the solvent afforded the title compound as an yellow oil.

Yield: 130 mg (43%).

HPLC-MS (Method B): m/z=487 (M+1), R_(t)=2.97 min.

Example 788-(3-Aminoazepan-1-yl)-7-benzyl-3-methyl-3,7-dihydropurine-2,6-dione.TFA (78)

7-Benzyl-8-bromo-3-methyl-3,7-dihydropurine-2,6-dione (77A) (300 mg, 0.9mmol) and azepan-3-ylamine (307 mg, 2.7 mmol), and triethylamine (0.62ml, 4.5 mmol) were dissolved in NMP (3 ml) and the mixture was subjectedto microwaves (method F, 200° C., 300 W) for 30 minutes. To the reactionmixture was added 100 ml of water and 100 ml of dichloromethane, and theorganic layer was washed with 1N NaOH, and dried over magnesium sulfate.The solvents were evaporated and the crude product was purified bypreparative HPLC (method A1, Rt=6.53 min.). Evaporation of the solventafforded the title compound as an brown oil.

Yield: 30 mg (7%).

HPLC-MS (Method B): m/z=369 (M+1), R_(t)=1.53 min.

Example 792-(8-(3-Aminoazepan-1-yl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.TFA (79)

Step A:2-(8-Bromo-3-methyl-2,6-dioxo-1.2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.(79A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione andalpha-bromo-o-tolunitrile were reacted and purified as described in theGeneral procedure G, step A, to afford 79A as white crystals in 91%yield.

HPLC-MS (Method B): m/z=360 (M+1), R_(t)=2.54 min.

Step B:2-(8-(3-Aminoazepan-1-yl)-3-methyl-2,6-dioxo-1.2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile.TFA (79)

2-(8-Bromo-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl)benzonitrile(79A) (181 mg, 0,5 mmol) and azepan-3-ylamine (342 mg, 3 mmol), andtriethylamine (0.35 ml, 2.5 mmol) were dissolved in 20 ml of DMSO andthe mixture was subjected to microwaves (method F, 100° C., 300 W) forfour hours. To the reaction mixture was added 100 ml of water and 100 mlof dichloromethane, and the organic layer was separated and dried oversodium sulfate. The solvents were evaporated and the crude product waspurified by preparative HPLC (method A1, R_(t)=6.22 min.). Evaporationof the solvent afforded the title compound as an yellow oil.

Yield: 142 mg (56%).

HPLC-MS (Method B): m/z=394 (M+1), R_(t)=1.41 min.

Example 808-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.TFA (80)

Step A: 8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione(80A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-bromobenzyl bromidewere reacted and purified as described in the General procedure G, stepA, to afford 80A.

HPLC-MS (Method B): m/z=414 (M+), Rt=3.285 min.

Step B:8-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione.TFA (80)

8-Bromo-7-(2-bromobenzyl)-3-methyl-3,7-dihydropurine-2,6-dione (80A)(300 mg, 0,7 mmol) and azepan-3-ylamine (248 mg, 2,2 mmol), andtriethylamine (0.5 ml, 3,6 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 30minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was separated and dried oversodium sulfate. The solvents were evaporated and the crude product waspurified by preparative HPLC (method A1, Rt=7.17 min.). Evaporation ofthe solvent afforded the title compound as an brown oil.

Yield: 138 mg (34%).

HPLC-MS (Method B): m/z=447 (M+), R_(t)=1.82 min.

Example 818-(3-Aminoazepan-1-yl)-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione.TFA (81)

Step A:8-Bromo-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione(81A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and2-(trifluoromethyl)benzyl bromide were reacted and purified as describedin the General procedure G, step A, to afford 81A as white crystals in69% yield.

HPLC-MS (Method B): m/z=403 (M+), Rt=3.54 min.

Step B:8-(3-Aminoazepan-1-yl)-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dioneTFA (81)

8-Bromo-3-methyl-7-(2-trifluoromethylbenzyl)-3,7-dihydropurine-2,6-dione(81A) (300 mg, 0,7 mmol) and azepan-3-ylamine (255 mg, 2,2 mmol), andtriethylamine (0.5 ml, 3,7 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 10minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was washed with 1N NaOH, anddried over sodium sulfate. The solvents were evaporated and the crudeproduct was purified by preparative HPLC (method A1, R_(t)=7.42 min.).Evaporation of the solvent afforded the title compound as a brown oil.

Yield: 96 mg (23%).

HPLC-MS (Method B): m/z=437 (M+1), R_(t)=2.30 min.

Example 828-(3-Aminoazepan-1-yl)-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.TFA (82)

Step A: 8-Bromo-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2.6-dione(82A)

8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-methylbenzyl bromidewere reacted and purified as described in the General procedure G, stepA, to afford 82A as white crystals in 79%.

HPLC-MS (Method B): m/z=351 (M+2), Rt=3.14 min.

Step B:8-(3-Aminoazepan-1-yl)-3-methyl-7-(2-methylbenzyl)-3.7-dihydropurine-2,6-dione.TFA (82)

8-Bromo-3-methyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione (82A)(300 mg, 0,86 mmol) and azepan-3-ylamine (294 mg, 2,6 mmol), andtriethylamine (0.6 ml, 4.3 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 3minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was washed with 1 N NaOH, anddried over sodium sulfate. The solvents were evaporated and the crudeproduct was purified by preparative HPLC (method A1, Rt=6.93 min.).Evaporation of the solvent afforded the title compound as yellowcrystals.

Yield: 201 mg (47%).

HPLC-MS (Method B): m/z=383 (M+1), R_(t)=2.06 min.

Example 838-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dione.TFA (83)

Step A:7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(83A)

8-Chlorotheophylline and 2-bromobenzyl bromide were reacted and purifiedas described in the General procedure CC, step A, to afford 83A as whitecrystals in 57%.

HPLC-MS (Method B): m/z=385 (M+2), Rt=3.77 min.

Step B:8-(3-Aminoazepan-1-yl)-7-(2-bromobenzyl)-1,3-dimethyl-3,7-dihydropurine-2,6-dioneTFA (83)

7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(83A) (300 mg, 0,8 mmol) and azepan-3-ylamine (268 mg, 2,3 mmol), andtriethylamine (0.5 ml, 3.9 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 15minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was washed with 1N NaOH, anddried over sodium sulfate. The solvents were evaporated and the crudeproduct was purified by preparative HPLC (method A1, R_(t)=7.76 min.).Evaporation of the solvent afforded the title compound as a brown oil.

Yield: 243 mg (54%).

HPLC-MS (Method B): m/z=461 (M+), R_(t)=2.32 min.

Example 842-[8-(3-Aminoazepan-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrile.TFA (84)

Step A:7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3.7-dihydropurine-2,6-dione(84A)

8-Chlorotheophylline and alpha-bromo-o-tolunitrile were reacted andpurified as described in the General procedure C, step A, to afford(84A) as white crystals in 66%.

HPLC-MS (Method B): m/z=330 (M+1), Rt=2.93 min.

Step B:2-[8-(3-Aminoazepan-1-yl)-1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-ylmethyl]benzonitrileTFA (84)

7-(2-Bromobenzyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione(84A) (300 mg, 0,9 mmol) and azepan-3-ylamine (312 mg, 2,7 mmol), andtriethylamine (0.6 ml, 4.6 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 30minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was washed with 1 N NaOH, anddried over sodium sulfate. The solvents were evaporated and the crudeproduct was purified by preparative HPLC (method A1, Rt=6.76 min.).Evaporation of the solvent afforded the title compound as a brown oil.

Yield: 268 mg (56%).

HPLC-MS (Method B): m/z=408 (M+1), R_(t)=1.95 min.

Example 858-(3-Aminoazepan-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione.TFA (85)

Step A:8-Chloro-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione(85A)

8-Chlorotheophylline and 2-methylbenzyl bromide were reacted andpurified as described in the General procedure C, step A, to afford 85Aas white crystals in 86%.

HPLC-MS (Method B): m/z=319 (M+1), Rt=3.76

Step B:8-(3-Aminoazepan-1-yl)-1,3-dimethyl-7-(2-methylbenzyl)-3.7-dihydropurine-2.6-dione.TFA (85)

8-Chloro-1,3-dimethyl-7-(2-methylbenzyl)-3,7-dihydropurine-2,6-dione(85A) (300 mg, 0,9 mmol) and azepan-3-ylamine (322 mg, 2,8 mmol), andtriethylamine (0.7 ml, 4.7 mmol) were dissolved in 3 ml of DMSO and themixture was subjected to microwaves (method F, 200° C., 300 W) for 10minutes. To the reaction mixture was added 100 ml of water and 100 ml ofdichloromethane, and the organic layer was washed with 1 N NaOH, anddried over sodium sulfate. The solvents were evaporated and the crudeproduct was purified by preparative HPLC (method A1, R_(t)=7.5 min.).Evaporation of the solvent afforded the title compound as a brown oil.

Yield: 312 mg (65%).

HPLC-MS (Method B): m/z=397 (M+1), R_(t)=2.04 min.

Example 868-(3-Amino-azepan-1-yl)-7-(2-chloro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione,TFA (86)

8-Chloro-7-(2-chloro-benzyl)-1,3-dimethyl-3,7-dihydro-purine-2,6-dione(0.34 g, 1 mmol), azepan-3-ylamine (0.34 g, 3 mmol), TEA (0.51 g, 5mmol) were mixed in 2-propanol (20 ml) and the mixture was subjected tomicrowaves (method F, 120° C.) for 4 hours. The reaction mixture wasevaporated and purified twice by preparative HPLC (method A1) to givethe title compound as white crystals.

Yield: 340 mg (64%).

¹H-NMR (DMSO-d₆, 300 MHz) δ: 9.3 (br s, 1H), 8.6 (br s, 2H), 7.4 (m,1H), 7.2 (m, 2H), 6.9 (m, 1H), 5.5 (q, 2H), 3.9 (m, 1H), 3.55-3.75 (m,3H), 3.45 (s, 3H), 3.3 (s, 3H), 2.9 (m, 1H), 2.25 (m, 1H), 1.85 (m, 1H),1.6 (m, 2H), 1.3 (m, 2H).

¹³C-NMR(CDCl₃)₆: 155.04, 154.42, 151.73, 133.87, 131.98, 130.07, 129.56,127.80, 126.81, 105.51, 55.15, 54.18, 51.70, 48.11, 31.18, 30.79, 30.07,28.25, 22.42.

Example 87 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide

¹H-NMR (DMSO-d₆, 300 MHz) δ: 10.80 (s, 1H), 8.32(s, 1H), 7.95(s, 4H),7.75(s, 1H), 7.51(s, 1H), 7.31(s, 2H), 7.10(s, 1H), 6.87(s, 1H), 5.40(s,2H), 4.65(s, 2H), 3.61(s, 1H), 3.45(s, 3H), 3.31(s, 1H), 3.13(s, 2H),2.87(s, 1H), 2.43(s, 1H), 1.93(s, 1H), 1.73(s, 1H), 1.50(s, 2H).

HPLC-MS (Method B): m/z=535 (M+1), Rt=2.059 min.

Example 88 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclohexyl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.95 (br, 3H), 7.83 (d, 1H), 7.51 (m, 1H),7.24-7.37 (m, 1H), 6.86 (d, 1H), 5.39 (s, 2H), 4.33 (s, 2H), 3.59 (d,1H), 3.47 (s, 3H), 3.31-3.40 (m, 3H), 1.89-1.97 (m, 1H), 1.59-1.79 (m,2.5H), 1.42-1.59 (m, 2.5H), 1.04-1.30 (m, 6H)

Example 89 General Procedure (H) (R)8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-1-(2-oxo-2-pyrrolidin-1-yl-ethyl)-3,7-dihydro-purine-2,6-dione

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.95 (br, 3H), 7.50 (d, 1H), 7.31 (m, 2H),6.83 (d, 1H), 5.38 (s, 2H), 4.50 (s, 2H), 3.59 (d, 1H), 3.42-3.50 (m,4H), 3.31-3.42 (br, 2H), 3.30 (s, 1H), 3.22-3.28 (m, 1H), 3.08-3.18 (m,2H), 2.99 (s, 1H), 2.83-2.92 (m, 1H), 1.85-1.97 (m, 2.5H), 1.70-1.81 (m,2.5H), 1.43-1.58 (m, 2H)

Example 90 General Procedure (H) (R)2-[8-(3-Aminopiperidin-1-yl)-7-(2-chlorobenzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclopentylacetamide.TFA

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.96 (s, 4H), 7.52 (d, 1H), 7.25-7.38 (m,2H), 6.83 (d, 1H), 5.40 (s, 2H), 4.33 (s, 2H), 3.92 (q, 1H), 3.42 (s,3H), 3.25-3.37 (m, 1H), 3.05-3.17 (m, 2H), 2.85 (t, 1H), 1.88-1.96 (m,1H), 1.70-1.81 (m, 4H), 1.56-1.70 (m, 3H), 1.42-1.55 (m, 5H), 1.30-1.40(m, 3H).

Example 91 General Procedure (H)

2-[8-(3-(R)Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(1-aza-bicyclo[2.2.2]oct-3-yl)-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 9.50 (s, 1H), 8.41 (d, 1H), 7.99 (br, 3H),7.50 (d, 1H), 7.23-7.39 (m, 2H), 6.83 (d, 1H), 5.41 (s, 2H), 4.43 (dd,2H), 4.03 (m, 1H), 3.54-3.64 (m, 1H), 3.31-3.51 (br, 6H), 3.31 (s, 1H),3.05-3.25 (m, 4H), 2.98 (s, 1H), 2.81-2.93 (m, 1H), 1.62-2.10 (m, 6H),1.41-1.58 (m, 2H), 1.13-1.27 (m, 1H)

Example 92 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide

¹H-NMR (MeOD, 300 MHz) δ: 7.865 (d, 1H), 7.505 (d, 1H), 7.40-7.22 (m,3H), 7.16-7.08 (m, 1H), 6.91-6.84 (m, 1H), 5.40 (s, 2H), 4.75 (s, 2H),6.65-3.54 (m, 1H), 3.45 (s, 3H), 3.18-3.04 (m, 3H), 2.92-2.79 (m, 1H),1.97-1.86 (m, 1H), 1.82-1.65 (m, 1H), 1.60-1.40 (m, 2H).

HPLC-MS (Method B): m/z=539 (M+1) Rt=1.836 min.:

Example 93 General Procedure (H)

(R,R)8-(3-Amino-piperidin-1-yl)-7-(2-chloro-benzyl)-1-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-3-methyl-3,7-dihydro-purine-2,6-dione

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7,95 (br, 3H), 7.50 (d, 1H), 7.25-7.38 (m,2H), 6.84 (d, 1H), 5.38 (s, 2H), 4.39-4.62 (m, 2H), 4.51 (s, 0.5H), 4.25(s, 0.5H), 3.49-3.65 (m, 2H), 3.45 (s, 3H), 3.07-3.31 (m, 3H), 2.99 (s,1H), 2.83-2.92 (m, 1H), 1.69-2.01 (m, 3H), 1.43-1.58 (m, 2H)

Example 94 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 10.77 (s, 1H), 8.32 (s, 1H), 7.95 (br, 3H),7.71-7.85 (m, 1H), 7.23-7.39 (m, 4H), 7.13-7.23 (m, 2H), 7.06-7.13 (m,1H), 5.37 (s, 2H), 4.70 (s, 2H), 3.54-3.65 (m, 1H), 3.12-3.26 (m, 1H),3.02-3.12 (m, 1H), 2.98 (s, 1H), 2.80-2.95 (m, 1H), 1.90-2.00 (m, 1H),1.70-1.82 (m, 1H), 1.45-1.61 (m, 2H)

Example 95 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclohexyl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.96 (s, 3H), 7.85 (d, 1H), 7.24-7.40 (m,3H), 7.18 (d, 2H), 5.36 (s, 2H), 4.37 (s, 2H), 3.53-3.62 (m, 1H), 3.40(s, 3H), 3.11-3.24 (m, 1H), 3.00-3.11 (m, 1H), 2.97 (s, 1H), 2.79 (m,1H), 1.89-2.01 (m, 1H), 1.61-1.82 (m, 5H), 1.44-1.61 (m, 3H), 1.05-1.31(m, 6H)

Example 96 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-cyclopentyl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.87-8.03 (m, 4H), 7.24-7.39 (m, 3H), 7.18(d, 2H), 5.37 (s, 2H), 4.37 (s, 2H), 3.91-4.00 (m, 1H), 3.57 (d, 1H),3.40 (s, 3H), 3.12-3.23 (m, 1H), 3.01-3.10 (m, 1H), 2.99 (s, 1H),2.79-2.88 (m, 1H), 1.90-2.01 (m, 1H), 1.70-1.84 (m, 2H), 1.56-1.70 (m,2H), 1.42-1.56 (m, 4H), 1.30-1.42 (m, 2H).

Example 97 General Procedure (H)2-[8-(3-(R)-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(1-aza-bicyclo[2.2.2]oct-3-yl)-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 9.48 (br, 1H), 8.43 (d, 1H), 7.98 (br, 3H),7.24-7.38 (m, 3H), 7.17 (d, 2H), 5.36 (s, 2H), 4.47 (dd, 2H), 4.05 (br,1H), 3.54-3.66 (m, 2H), 3.40 (s, 3H), 3.11-3.26 (m, 4H), 3.00-3.11 (m,1H), 2.99 (s, 1H), 2.88-2.97 (m, 1H), 2.79-2.88 (m, 1H), 1.91-2.08 (m,3H), 1.64-1.91 (m, 3H), 1.45 (m, 2H)

Example 98 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.76 (br, 3H), 7.89 (d, 1H), 7.24-7.40 (m,5H), 7.13-7.24 (m, 3H), 5.38 (s, 2H), 4.82 (s, 2H), 3.56-3.65 (m, 1H),3.40 (s, 3H), 3.14-3.23 (m, 1H), 3.02-3.11 (m, 1H), 2.99 (s, 1H),2.80-2.93 (m, 1H), 1.91 (m, 1H), 1.71-1.83 (m, 1H), 1.46-1.60 (m, 2H)

Example 99 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-3-yl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 10.52 (br, 1H), 8.76 (s, 1H), 8.31 (d, 1H),7.85-8.05 (m, 5H), 7.56-7.70 (m, 2H), 7.38-7.46 (m, 1H), 7.24-7.38 (m,3H), 7.19 (d, 2H), 5.38 (s, 2H), 4.67 (s, 2H), 3.52 (m, 1H), 3.45 (s,3H), 3.13-3.25 (m, 1H), 3.01-3.13 (m, 1H), 2.98 (s, 1H), 2.81-2.94 (m,1H), 1.90-2.01 (m, 1H), 1.70-1.82 (m, 1H), 1.45-1.61 (m, 2H)

Example 100 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(6-amino-pyridin-2-yl)-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.85-8.02 (m, 4H), 7.59-7.68 (m, 1H),7.45-7.55 (m, 1H), 7.32-7.43 (m, 1H), 7.07 (d, 1H), 6.18-6.24 (m, 1H),5.53 (s, 2H), 4.49 (s, 2H), 3.57 (m, 1H), 3.44 (s, 3H), 3.29 (s, 1H),3.07-3.23 (m, 2H), 2.95 (s, 3H), 2.94-2.88 (M, 1H), 1.89 (m, 1H),1.74-1.85 (m, 1H), 1.49 (m, 2H)

Example 101 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-pyridin-2-yl-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 10.74 (s, 1H), 8.32 (s, 1H), 7.83-8.05 (m,5H), 7.70-7.83 (m, 1H), 7.59-7.70 (m, 1H), 7.45-7.59 (m, 1H), 7.03-7.17(m, 2H), 5.54 (s, 2H), 4.64 (s, 2H), 3.54-3.69 (m, 1H), 3.40 (s, 3H),3.18-3.50 (m, 4H), 3.0 (s, 3H), 1.87 (m, 1H), 1.70-1.87 (m, 1H),1.47-1.64 (m, 2H).

Example 102 General Procedure (H) (R)2-[8-(3-Amino-piperidin-1-yl)-7-(2-cyano-benzyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-purin-1-yl]-N-(3-hydroxy-pyridin-2-yl)-acetamide

¹H-NMR (DMSO-d₆, 400 MHz) δ: 7.96 (br, 3H), 7.84-7.90 (m, 2H), 7.65 (t,1H), 7.49 (t, 1H), 7.32 (d, 1H), 7.13-7.19 (m, 1H), 7.08 (d, 1H), 5.52(s, 2H), 4.75 (s, 2H), 3.53-3.61 (m, 1H), 3.40 (s, 3H), 3.08-3.23 (m,2H), 3.05 (s, 2H), 2.90-3.05 (M, 1H), 1.90-2.00 (m, 1H), 1.72-1.84 (m,1H), 1.48-1.65 (m, 2H)

Example 103 General Procedure (E) (R)8-(3-Amino-piperidin-1-yl)-1,3-dimethyl-7-thiophen-2-ylmethyl-3,7-dihydro-purine-2,6-dione

¹H-NMR (CDCl₃, 200 MHz) δ: 8.40 (br. 3H), 7.18 (d, 1H), 7.03 (d, 1H),6.88 (m, 1H), 5.5 (s, 2H), 3.70-3.55 (m, 2H), 3.45 (s, 3H), 3.37 (s,3H), 3.30-3.00 (m, 3H), 2.20-1.55 (m, 4H).

¹³C-NMR (CDCl₃, 200 MHz) 8:155.15, 154.73, 151.60, 147.04, 138.04,127.08, 127.01, 126.18, 104.75, 52.16, 51.44, 46.71, 43.53, 29.73,27.99, 27.65, 21.07.

1. A compound of formula I

wherein A may be attached at either N¹ or at N² to the purine system and n is one or two, m is one, two, or three, R¹ is aryl optionally substituted with one or more R² independently or heteroaryl optionally substituted with one or more R² independently, R² is H, C₁-C₇ alkyl, C₂-C₇ alkenyl, C₂-C₇ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, —NHCOR³, —NHSO₂R³, —SR³, —SOR³, —SO₂R³, —OCOR³, —CO₂R⁴, —CON(R⁴)₂, —CSN(R⁴)₂, —NHCON(R⁴)₂, —NHCSN(R⁴)₂, —NHCONNH₂, —SO₂N(R⁴)₂, —OR⁴, cyano, nitro, or halogen, wherein each alkyl, alkenyl, alkynyl, cycloalkyl and cycloheteroalkyl is optionally substituted with one or more R³ independently, R³ is Halogen, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, aryl, heteroaryl, —OR¹¹, —N(R¹¹)₂, or —SR¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl is substituted with one or more R¹¹ independently, R⁴ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, aryl-C₁-C₅ alkyl, heteroaryl, or heteroaryl-C₁-C₅ alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, aryl-C₁-C₅ alkyl, heteroaryl, and heteroaryl-C₁-C₅ alkyl is substituted with one or more R¹¹ independently, R⁵ is H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl-C₁-C₅ alkyl, C₃-C₇ cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl, heteroaryl, aryl-C₁-C₅ alkyl, heteroaryl-C₁-C₅ alkyl, —OR⁷, or —[(CH₂)_(n)—O]_(p)-alkyl, wherein o and p are 1-3 independently, and wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-C₁-C₅ alkyl, cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl, aryl-C₁-C₅ alkyl, heteroaryl, and heteroaryl-C₁-C₅ alkyl is optionally substituted with one or more substituents independently selected from R⁷ or R¹¹ independently, R⁶ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, aryl-C₁-C₅ alkyl, heteroaryl-C₁-C₅ alkyl, or C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, C₃-C₇ cycloheteroalkyl-C₁-C₅ alkyl, aryl, aryl-C₁-C₅ alkyl, heteroaryl, aryl-C₁-C₅ alkyl, and heteroaryl-C₁-C₅ alkyl is optionally substituted with one or more R¹¹ independently, R⁷ is H, ═O, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, —OR¹¹, —N(R¹¹)₂, or —SR¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹¹ independently, R⁸ is C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, C₂-C₁₀ alkynyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, aryl, heteroaryl, —OR¹¹, —N(R¹¹)₂, or —SR¹¹, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹¹ independently, R⁹ and R¹⁰ is independently H, C₁-C₁₀ alkyl optionally substituted with one or more R⁸ independently, or halogen, R¹¹ is H, —CF₃, —CCl₃, —OCF₃, —OMe, cyano, halogen, —OH, —COMe, —CONH₂, —CONHMe, —CONMe₂, —NO₂, C₁-C₁₀ alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, or C₃-C₇ cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹² independently, R¹² is H, C₁-C₁₀ alkyl, —CF₃, —CCl₃, —OCF₃, —OMe, cyano, halogen, —OH, —COMe, —CONH₂, —CONHMe, —CONMe₂, —NH₂, or —NO₂ If R⁹ and R¹⁰ is C₁-C₁₀ alkyl, they may be connected to form a cyclopropyl ring, if two R⁴ or two R¹¹ are attached to the same nitrogen, they may be connected to form a 3-to 7-membered ring, or any tautomeric form or any optical isomer or mixture of optical isomers, including a racemic mixture, or a salt thereof with a pharmaceutically acceptable acid or base.
 2. A compound according to claim 1, wherein R¹ is aryl optionally substituted with one or more R² independently.
 3. A compound according to claim 2, wherein R¹ is phenyl substituted with one or more R² independently.
 4. A compound according to claim 2, wherein R¹ is aryl.
 5. A compound according to claim 4, wherein R¹ is phenyl.
 6. A compound according claim 1, wherein R² is C₁-C₇ alkyl, C₂-C₇ alkynyl, cyano, or halogen, wherein each alkyl and alkynyl is optionally substituted with one or more R³ independently.
 7. A compound according to claim 6 wherein R² is C₁-C₇ alkyl, C₂-C₇ alkynyl, cyano, or halogen.
 8. A compound according to claim 7 wherein R² is methyl.
 9. A compound according to claim 7 wherein R² is cyano or halogen.
 10. A compound according to claim 1, wherein R³ is C₁-C₁₀ alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R¹¹ independently.
 11. A compound according to claim 10 wherein R³ is C₁-C₁₀ alkyl or aryl.
 12. A compound according to claim 11 wherein R³ is methyl or phenyl.
 13. A compound according to claim 1, wherein R³ is halogen.
 14. A compound according to claim 1, wherein R⁴ is H, C₁-C₁₀ alkyl or aryl, wherein each alkyl or aryl is substituted with one or more R¹¹ independently.
 15. A compound according to claim 14 wherein R⁴ is H, C₁-C₁₀ alkyl or aryl.
 16. A compound according to claim 15 wherein R⁴ is H, methyl or phenyl.
 17. A compound according to claim 1, wherein R⁵ is H, C₁-C₁₀ alkyl, aryl-C₁-C₅ alkyl, or heteroaryl-C₁-C₅ alkyl, wherein each alkyl, aryl-C₁-C₅ alkyl and heteroaryl-C₁-C₅ alkyl is optionally substituted with one or more R⁷ independently.
 18. A compound according to claim 17, wherein R⁵ is H or C₁-C₁₀ alkyl optionally substituted with one or more R⁷ independently.
 19. A compound according to claim 18, wherein R⁵ is H or C₁-C₁₀ alkyl.
 20. A compound according to claim 19, wherein R⁵ is H.
 21. A compound according to claim 19 wherein R⁵ is methyl.
 22. A compound according to claim 1, wherein R⁶ is C₁-C₁₀ alkyl, aryl-C₁-C₅ alkyl, or heteroaryl-C₁-C₅ alkyl, wherein each alkyl, aryl-C₁-C₅ alkyl and heteroaryl-C₁-C₅ alkyl is optionally substituted with one or more R¹¹ independently.
 23. A compound according to claim 22, wherein R⁶ is C₁-C₁₀ alkyl, aryl-C₁-C₅ alkyl, or heteroaryl-C₁-C₅ alkyl.
 24. A compound according to claim 22, wherein R⁶ is C₁-C₁₀ alkyl optionally substituted with one or more R¹¹ independently.
 25. A compound according to claim 24 wherein R⁶ is C₁-C₁₀ alkyl.
 26. A compound according to claim 25 wherein R⁶ is methyl.
 27. A compound according to claim 1, wherein R⁷ is H, ═O, aryl, heteroaryl, OR¹¹, N(R¹¹)₂, SR¹¹, wherein each aryl and heteroaryl is optionally substituted with one or more R¹¹ independently.
 28. A compound according to claim 27 wherein R⁷ is H, ═O, C₁-C₁₀ alkyl, —OR¹¹, —N(R¹¹)₂, —SR¹¹.
 29. A compound according to claim 28 wherein R⁷ is H, ═O, —OR¹¹, or —N(R¹¹)₂.
 30. A compound according to claim 29, wherein R⁷ is H, ═O, or —N(R¹¹)₂.
 31. A compound according to claim 30, wherein R⁷ is =0 or —N(R¹¹)₂.
 32. A compound according to claim 1, wherein R⁸ is aryl or heteroaryl, wherein each aryl and heteroaryl is optionally substituted with one or more R¹¹ independently.
 33. A compound according to claim 32, wherein R⁸ is aryl or heteroaryl.
 34. A compound according to claim 33, wherein R⁸ is phenyl.
 35. A compound according to claim 1, wherein R⁹ is H, C₁-C₁₀ alkyl, or halogen.
 36. A compound according claim 35, wherein R⁹ is H.
 37. A compound according to claim 1, wherein R¹⁰ is H, C₁-C₁₀ alkyl, or halogen.
 38. A compound according claim 37 wherein R¹⁰ is H.
 39. A compound according to claim 1, wherein R¹¹ is H, —CF₃, cyano, halogen, —OH, —NO₂, C₁-C₁₀ alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹² independently.
 40. A compound according to claim 39, wherein R¹¹ is H, halogen, —OH, C₁-C₁₀ alkyl, aryl, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹² independently.
 41. A compound according to claim 40, wherein R¹¹ is H, halogen, —CH₃, aryl, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with one or more R¹² independently.
 42. A compound according to claim 41, wherein R¹¹ is H, halogen, —CH₃, heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each alkyl, cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R¹² independently.
 43. A compound according to claim 42, wherein R¹¹ is H, halogen, or —CH₃.
 44. A compound according to claim 42, wherein R¹¹ is heteroaryl, C₃-C₇ cycloalkyl, C₃-C₇ cycloheteroalkyl, wherein each cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R¹² independently.
 45. A compound according to claim 44, wherein R¹¹ is selected from the group consisting of pyridine, cyclopentane, cyclohexane, and pyrrolidine, wherein each cycloalkyl, cycloheteroalkyl, and heteroaryl is optionally substituted with one or more R¹² independently.
 46. A compound according to claim 1, wherein R¹² is H, C₁-C₁₀ alkyl, —CF₃, cyano, halogen, —OH, —COMe, —NH₂, —NO₂.
 47. A compound according to claim 46, wherein R¹² is H, —CF₃, cyano, halogen, —OH, —NH₂.
 48. A compound according to claim 47, wherein R¹² is —OH or —NH₂.
 49. A compound according to claim 1, wherein n is two.
 50. A compound according to claim 1, wherein n is one.
 51. A compound according to claim 1, wherein m is two or three.
 52. A method for treating type II diabetes, said method comprising administering to a patient in need thereof an effective amount for said treatment of a compound according to claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form thereof.
 53. A pharmaceutical composition for treatment or prevention of type 2 diabetes, comprising (i) a compound according to claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric form and (ii) one or more pharmaceutically acceptable carriers or diluents 